The driving force for solution crystallization is the supersaturation, the concentration of the crystallizing species in solution over the concentration when the solution is at equilibrium with the solid phase. It is observed that macromolecule crystals typically nucleate and grow at higher supersaturations than found for small molecules. The equilibrium concentration at a defined set of conditions is a fixed point in the phase diagram and as such can be thermodynamically evaluated. The problems of working with biomolecules, such as their usually limited supply, structural flexibility, and limited stability in solution, exacerbate the problems of obtaining solubility data. This chapter, presented in four sections, focuses on proteins. Section 1 is a general review of protein crystallization and the importance of solubility in crystallization studies. Section 2 is a review of the methods that have been developed for determining protein solubility. These can be broadly differentiated into solution-based and optical approaches. As a general rule, the optimal methods for determining solubility are those that approach it from both directions, from over- and undersaturated conditions. Section 3 covers solubility data analysis and the parameters that are derived from this analysis. Section 4 reviews another commonly derived parameter, the second virial coefficient, B22.