Protein crystallization remains a key limiting step in the characterization of the atomic structures of proteins and their complexes by X-ray diffraction methods. Current data indicate that standard screening procedures applied to soluble well folded prokaryotic proteins yield X-ray diffraction crystals with an approximately 20% success rate and for eukaryotic proteins this figure may be significantly lower. Protein crystallization is predominantly dependent on entropic effects and the driving force appears to be the release of ordered water from the sites of crystal contacts. This is countered by the entropic cost of ordering of protein molecules and by the loss of conformational freedom of side chains involved in the crystal contacts. Mutational surface engineering designed to create patches with low conformational entropy and thereby conducive to formation of crystal contacts promises to be an effective tool allowing direct enhancement of the success rate of macromolecular crystallization.