The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chemistry screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.