In this paper we first describe our effort in developing a grafting approach to understand site-specific calcium binding affinities using calmodulin as an example. Next we discuss our progress in predicting EF-hand calcium binding sites in various biological systems such as bacteria and virus systems. We then report our results following application of the grafting approach to probe calcium binding capabilities in streptococcal hemoprotein receptor (Shr) of Streptococcus pyrogenes and the nonstructural protein of Sindbis virus.