Employing detailed atomistic modeling we study the mechanismsbehind ion binding to proteins and other biomolecules and concludethat (1) small, hard ions bind via direct ion pairing to charged surfacegroups and (2) large, soft ions bind to nonpolar groups via a solventassisted attraction. Our predictions are in qualitative agreementwith bulk solution data and may provide an important clue for thebasic understanding of ion-specific effects in biological systems.