The loss of insulin-producing beta-cells is the central pathological event in type 1 and 2 diabetes, which has led to efforts to identify molecules to promote beta-cell proliferation, protection, and imaging. However, the lack of beta-cell specificity of these molecules jeopardizes their therapeutic potential. A general platform for selective release of small-molecule cargoes in beta-cells over other islet cells ex vivo or other cell-types in an organismal context will be immensely valuable in advancing diabetes research and therapeutic development. Here, we leverage the unusually high Zn(II) concentration in beta-cells to develop a Zn(II)-based prodrug system to selectively and tracelessly deliver bioactive small molecules and fluorophores to beta-cells. The Zn(II)-targeting mechanism enriches the inactive cargo in beta-cells as compared to other pancreatic cells; importantly, Zn(II)-mediated hydrolysis triggers cargo activation. This prodrug system, with modular components that allow for fine-tuning selectivity, should enable the safer and more effective targeting of beta-cells.