Many reactions in organic chemistry are extremely complex, with large multivariate parameter spaces and multiple possible mechanistic pathways. During development of synthetic routes toward investigational Active Pharmaceutical Ingredients (APIs), my group at GlaxoSmithKline used both high-throughput experimentation and reaction progress analysis in order to map and understand complex reactions. High-throughput experimentation allows for simultaneous interrogation of multiple reaction parameters, illuminating aspects to chemical reactivity that are not apparent during traditional one-variable-at-a-time experimental designs. By combining these insights with kinetic monitoring and stoichiometric reactivity, we have been able to rapidly develop and optimize many complex transformations for API synthesis. Several case studies will be presented, with an emphasis on how insights from target-based API synthesis can lead to more general advances in synthetic methodology.