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In PNAS, Urquidi et al. (1) combine techniques to induce nucleation in an optical trap (2), with Raman microspectroscopy (3) to monitor the steps before, during, and after crystal nucleation. Nucleation is the first step in the formation of a new material from less stable starting materials. For crystallization, the starting material is a supersaturated solute, that is, a solution concentrated beyond its solubility limit. Depending on the solute concentration, the thermodynamically allowed products may include multiple crystal structures (“polymorphs”) (4) each comprising the same solute molecule or compound. Starting with Ostwald (5), generations of scientists have attempted to understand and predict which material will emerge from nucleation and growth. The answer is complicated (6, 7). The process is somewhat like survival of the fittest in the materials context. A given phase can win in three ways: 1) by getting a head start at the nucleation stage; 2) by outracing the competition during growth; or 3) by being the most thermodynamically stable, if it survives to the ripening and/or coarsening endgame. Among these three processes, nucleation is notoriously difficult to study because it is a rare event (8); that is, it occurs at random locations, occurs at random times, and yields a nanoscopic cluster that usually cannot be seen until it grows far beyond its size at inception. By enhancing the solute concentration at a focused laser spot, and monitoring that spot with Raman spectroscopy, the technique by Urquidi et al. (1) stands to provide unprecedented insight on nucleation mechanisms. Until recently, ideas about crystal nucleation mechanisms were built around the classical nucleation theory (CNT) (9). According to the classical theory, nuclei are nanoscopic, equilibrium-shaped clusters with macroscopic crystal structure (10). The theory further assumes that nuclei form and redissolve via a series of monomer attachment and detachment events (11, 12), until a rare fluctuation generates a nucleus large enough for the chemical potential driving force to overcome surface forces (more generally, forces arising from the excess free energy). A few alternative nucleation pathways were recognized, but these involved external agents, for example, collision-induced attrition to generate postcritical fragments (13), ordering and enrichment at charged surfaces (14), or clustering around impurities like charged polymers in solution (15). In 1997, with rare event simulation methods leading the way (16), it became clear that crystals could nucleate via local density fluctuations, long-lived droplets, and amorphous intermediates (17–20). State-of-the-art methods like atomic force microscopy (AFM) and in situ liquid phase transmission electron microscopy (LP-TEM) methods provide stunning footage of nucleation (19), including many examples of two-step nucleation (21) and other nonclassical nucleation pathways (22). Initial rumors about the death of CNT were sometimes exaggerated, but a more nuanced view has emerged in which the classical pathway is just one of many potential mechanisms, as shown in Fig. 1. The challenge ahead is to understand which factors can help anticipate the dominant mechanism, and to develop predictive rate theories for each of the various nonclassical mechanisms. For mechanistic studies, AFM is limited to interfacial processes, and the 100-nm-thick LP-TEM cell is also quite different from the bulk solution. For example, the high surface to volume ratio, cluster adhesion effects, and reactions driven by electron irradiation (24) can potentially alter the dominant pathway. In view of these limitations, the study of Urquidi et al. (1) is a particularly important advance. Their single-crystal nucleation spectroscopy approach enriches the solute concentration in a focused laser spot. The locally elevated concentration accelerates nucleation while the rate remains negligible in the surrounding solution. There are no Fig. 1. Menagerie of nucleation mechanisms. Acronyms and symbols in the diagrams are as follows: CNT, classical nucleation; Hom, homogeneous (in solution) (9); Het, heterogeneous (at an interface) (9); 2°, secondary (from one existing particle to many) (13); 2SN, two-step nucleation (17); PNC, prenucleation cluster (20); and MSC, magic-sized cluster (long-lived metastable intermediates) (23). Nonclassical typically refers to all but the secondary (2°) mechanisms and the mechanisms labeled CNT.