Organisms have the ability to produce structures with superior characteristics as in the course of biomineralization. One of the most intriguing characteristics of biominerals is the existence of intracrystalline macromolecules. Despite several studies over the last two decades and efforts to mimic the incoporation of macromolecules synthetically, a fundamental understanding of the mechanism of incorporation is as yet lacking. For example, which of the common 20 amino acids are really responsible for the interaction with the mineral phase? Here a reductionist approach, based on high-resolution synchrotron powder diffraction and analytical chemistry, is utilized to screen all of these amino acids in terms of their incorporation into calcite. We showed that the important factors are amino-acid charge, size, rigidity and the relative pKa of the carboxyl and amino functional groups. It is also demonstrated that cysteine, surprisingly, interacts very strongly with the mineral phase and therefore, like acidic amino acids, becomes richly incorporated. The insights gained from this study shed new light on the incorporation of organic molecules into an inorganic host in general, and in particular on the biomineralization process.