Poor water solubility of active pharmaceutical ingredients (APIs) is a common challenge for drug product developers. Many marketed APIs are classified as BCS II/IV compounds, meaning they suffer from poor water solubility and/or low tissue permeability. For decades, scientists have relied on formulation techniques to enhance the bioavailability of APIs, and estimates predict that as many as 90% of API s in the development pipeline suffer from solubility or bioavailability challenges (many of which are complex APIs and biologics). We will review common methods for increasing solubility and bioavailability of BCS Class II/IV APIs, including phys. modification, chem. modification, encapsulation, and inclusion complexes. We will also explore the benefits of high energy media milling (AKA nanomilling)-a com.-validated solubility enhancement technique.