Injectable biodegradable and biocompatible copolymers of lactic and glycolic acid (PLGA) are an important advanced delivery system for week-to-month controlled release of hydrophobic drugs (e.g., from biopharmaceutical classification system class IV), which often display poor oral bioavailability. The basic principles and considerations to develop such microparticle formulations is reviewed here based on a comprehensive study of papers and patents from the beginnings of hydrophobic drug encapsulation in polylactic acid and PLGA up through the very recent literature. Challenges with the diversity of drug properties, microencapsulation methods, and organic solvents are evaluated in light of the precedence of commercialized formulations and with a focus on decreasing the time to lab-scale encapsulation of water-insoluble drug candidates in the early stage of drug development. The influence of key formulation variables on final microparticle characteristics, and how best to avoid undesired microparticle properties, is analyzed mechanistically. Finally, concepts are developed to manage the common issues of maintaining sink conditions for in vitro drug release assays of hydrophobic compounds. Overall, against the backdrop of an increasing number of new, poorly orally available drug entities entering development, microparticle delivery systems may be a viable strategy to rescue an otherwise undeliverable substance.