Solution stability of drug candidates in plasma, gastrointestinal fluids and bioassays is important in order to achieve low clearance, good oral bioavailability and have robust SAR. Screening of solution stability early in drug discovery can avoid pursuing hits with high risk of instability, prioritize chemical series, guide structural modification, and enhance the chance of project success. The conditions of solution stability methods are critical in generating relevant data and include: test compound concentration, enzyme source and preparation, limits of solubility, cosolvent, plasma protein binding effect, detection techniques (LC-UV vs. LC-MS), and what to detect (disappearance of parent vs. formation of degradants). Details of methodologies, applications, structure-stability relationships and case studies are discussed.