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From trafficking to maintenance Neurons are remarkably polarized in that proteins made in the cytosol often need to travel many tens or hundreds of cell body lengths along axons to their sites of action in the synapse. Axonal transport of these components is driven by molecular motors along axonal microtubules. Guedes-Dias and Holzbaur review the cell biology of axonal transport and highlight the roles this fundamental process plays in organismal health. Science, this issue p. eaaw9997 BACKGROUND Neurons are polarized cells with extreme geometries. Multiple dendrites and one axon generally emerge from a single cell body and establish synaptic contacts with their partners. Synaptic maintenance and plasticity rely on the active delivery of newly synthesized components to these sites, which may be localized up to a meter from the cell body. Cargos that are actively trafficked along the axon include synaptic vesicle precursors, mitochondria, signaling endosomes, autophagosomes, lysosomes, and mRNA granules. In axons, these cargos use cytoplasmic dynein and kinesin motors to navigate a uniformly polarized microtubule network to reach their destinations. In dendrites, microtubules are organized in a more complex, bipolar pattern that is effectively navigated by a distinct subset of neuronal motor proteins and is less understood overall. ADVANCES Traditionally, the meter-long axon of human lower motor neurons has been considered as an example of the long distances cargo must be conveyed from soma to synaptic terminal. Advances in connectomics and axonal tracing techniques are providing us with an increasingly accurate depiction of the morphology and size of axonal arbors in the central nervous system (CNS) and the many synaptic connections that mediate neuronal function. In humans, it is estimated that the axonal arbor of some neuronal populations in the CNS can range up to hundreds of meters in total length and may contain thousands of “en passant” synapses along its extent. Improved and complementary in vitro and in vivo imaging approaches are now allowing the elucidation of increasingly intricate mechanisms by which the activities of dynein and kinesin motors regulate organelle transport along axons. Recently, efforts have focused on identifying the adaptor proteins that specify motor-cargo selectivity and the regulatory mechanisms that govern the directed transport of cargo-carrying opposing motor proteins. In parallel, important advances are being made in our understanding of how the axonal microtubule network is organized and how changes at the microtubule level can affect motor activity to finely regulate axonal transport. A picture is now emerging whereby the exquisite interplay of several regulatory mechanisms functioning at multiple levels directs how and when motors initiate and terminate transport, and how molecular motors respond to local cues to deliver cargo with high precision along the axon. This type of targeted delivery is required to maintain essential neuronal functions such as synaptic activity. OUTLOOK The intracellular transport system in neurons is specialized to an extraordinary degree, enabling the delivery of critical cargo to sites in axons or dendrites that are far removed from the cell center. Distance is not the only challenge. Localized delivery of presynaptic components provides another layer of complexity that must be successfully navigated to maintain synaptic transmission. Innovative approaches to determine the mechanisms regulating axonal transport and cargo delivery, the number and lifetime of presynaptic components, and the metabolic requirements to maintain synaptic activity are required. These advances will be key to assembling a more comprehensive and quantitative framework of axonal transport and its central role in presynaptic operation. A growing number of mutations across the molecular machinery involved in axonal transport are being identified that cause a range of neurodevelopmental and neurodegenerative diseases. Both nerve injury and chemotherapy can also disrupt trafficking pathways in neurons. Hopefully, the mechanistic insights being developed now will provide a framework for the design of successful therapeutic interventions for both genetic and trauma-induced disruptions in axonal transport and synaptic function. Axonal transport drives cargo through extreme geometries. Neurons in the human central nervous system display highly complex axonal arbors that can branch thousands of times, reach hundreds of meters in total length, and contain hundreds of thousands of presynaptic sites distributed “en passant.” The axonal transport machinery supports synaptic function by delivering new synaptic vesicles to and removing aged organelles from presynaptic sites. The intracellular transport system in neurons is specialized to an extraordinary degree, enabling the delivery of critical cargo to sites in axons or dendrites that are far removed from the cell center. Vesicles formed in the cell body are actively transported by kinesin motors along axonal microtubules to presynaptic sites that can be located more than a meter away. Both growth factors and degradative vesicles carrying aged organelles or aggregated proteins take the opposite route, driven by dynein motors. Distance is not the only challenge; precise delivery of cargos to sites of need must also be accomplished. For example, localized delivery of presynaptic components to hundreds of thousands of “en passant” synapses distributed along the length of a single axon in some neuronal subtypes provides a layer of complexity that must be successfully navigated to maintain synaptic transmission. We review recent advances in the field of axonal transport, with a focus on conceptual developments, and highlight our growing quantitative understanding of neuronal trafficking and its role in maintaining the synaptic function that underlies higher cognitive processes such as learning and memory.