Is the 14-3-3 protein interactome a pharmacological gold mine for protecting β-cells? 14-3-3ζ can interact with proteins harboring specific binding motifs created by phosphorylated serine (Ser) or threonine (Thr) residues, and this results in a dynamic interactome that can be elucidated for identifying novel regulators of β-cell function, proliferation, or survival. For example, using cadaveric human islets from healthy donors or those from donors with type 2 diabetes, 14-3-3ζ–anchored protein complexes can be purified (A) and subjected to mass spectrometry (MS) (B) to elucidate the interactome of 14-3-3ζ, and the contributions of identified interactors could then be determined by high-throughput screening assays or genomic approaches to assess their roles in β-cell survival, proliferation, and insulin secretion (C).