The serine/threonine binding protein, 14-3-3, possesses a diverse array of client proteins. It is involved in the regulation of apoptosis through multiple interactions with proteins of the core mitochondrial machinery, pro-apoptotic transcription factors, and their upstream signaling pathways. 14-3-3 coordinates with survival kinases to inhibit multiple pro-apoptotic molecules. One prominent mechanism for the suppression of apoptosis is through 14-3-3-mediated sequestration of pro-apoptotic client proteins. On the other hand, cellular stresses appear to signal through the inhibition of 14-3-3 function to exert their pro-apoptotic effect. Global inhibition of 14-3-3/client protein interaction induces apoptosis, and stands as an attractive intervention in diseases involving overactive survival signaling pathways. Because dysregulation of 14-3-3 has been associated with poor survival of cancer patients, targeting 14-3-3 may provide a novel therapeutic approach for the treatment of cancer.