The aqueous solubility of a drug is one of the key physical properties that affect both its ADME profile and 'screenability' in HTS. This review critically surveys a range of methods that can be used to predict the solubility of a compound in water and presents some of the main issues that affect the applicability of different techniques. As ever, there are trade-offs to be made between the speed, accuracy and transparency of methods, but current programs can provide estimates to well within an order of magnitude in favourable cases. The need for new ways to predict solubility in more challenging systems (e.g. solvents such as DMSO and charged solutes) is discussed.