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In the last decade, the adoption of advanced three-dimensional (3D) cell culture technologies has accelerated in basic research, drug discovery, and development. This has occurred in parallel with the growing use of human cells derived from induced pluripotent stem cells (iPSCs), many of which can now be routinely cultured under standardized conditions. These two approaches allow the generation of authentic human cell lines that are more representative of the physiological environment found in vivo. Moreover, such cells may be isolated from individual patients, which facilitates their use in disease models for disease research, compound library screening, and lead optimization. In other words, when cultured under 3D conditions, human iPSCs clearly provide optimized systems that more accurately reflect disease-related target mutations, compound pharmacology, and toxicology. As one would anticipate, the field continues to rapidly evolve, particularly in terms of extending 3D cell culture systems to generate complex, multicellular systems in which cells are spatially arranged similarly to tissues in vivo. Indeed, the use of organoids and more complex organ systems is now extending into areas beyond fundamental research and entering the domains of lead optimization, including estimations of preclinical toxicity and potential metabolic liability. In this special collection, reviews and original research reports have been assembled to illustrate many of the points above. The collection begins with a two-part review that assesses the current role of human iPSCs when used in the context of 3D cell culture, including the generation of organoids. The first part emphasizes the role of these two techniques in drug discovery, particularly in the areas that bookend the workflow process, that is, identification of the drug target and optimization of the lead compound. The second part of the review focuses on the 3D culture of human iPSCs derived from patient tissues using spheroids and organoids and their use in disease modeling. Generally, human iPSCs clearly provide advantages for drug discovery over cell lines derived from traditional rodent or tumor sources. They can also be cultured with the desired genetic profile in unlimited, but reproducible, amounts for high-throughput screening (HTS). Furthermore, patient-derived human iPSCs can be differentiated to specific cell types endogenously expressing the molecular target of interest as well as other key tissues, such as liver, muscle, kidney, heart, or neurons, frequently used to screen for off-target drug effects. Part 1 of the review also emphasizes the use of human iPSCs in drug discovery. The article particularly highlights their use in neurodegenerative disease research, an area where few, if any, animal models exist for the sporadic forms of the diseases. The review also makes the point that human iPSCs find widespread utility in preclinical safety testing, given that in vitro and in vivo safety evaluation has historically been conducted using animal-derived models, many of which poorly translate to the clinic. Indeed, lead optimization can now be undertaken using cells not only from healthy individuals, but also from patients with different diseases, thereby allowing for the selection of compounds with lower side effect profiles in the specific patient population. The second part of the review illustrates that human iPSCs derived from tissues cultured in 3D spheroid and organoid systems can be used for both drug safety evaluation and drug discovery. 3D culture systems also allow better modeling of cells and cell interaction seen in tissue than is possible with two-dimensional culture systems. As importantly, 3D cell cultures can be long lived—in some cases for several weeks. This temporal aspect of cell culture (sometimes referred to as four-dimensional cell culture) is critical when modeling diseases that are slow to develop, such as neurodegenerative diseases, and when providing the possibility of chronic cell exposure to pharmacologically active compounds. The remainder of this special collection includes original research reports that illustrate in more detail the points above. The report by Wilson et al. describes a spheroid model of glioblastoma—a lethal brain cancer with low survival times following treatment. Common in vitro disease models do not recapitulate the features of human glioblastoma in vivo. This article describes the genomic characterization of nine patientderived, spheroid glioblastoma cell lines that model human 810819 JLAXXX10.1177/2472630318810819SLAS TECHNOLOGY: Translating Life Sciences InnovationEglen research-article2018