The incretin GIP is a major regulator of post-prandial insulin secretion in mammals. Recent studies in our laboratory, and others, have suggested that GIP is a potent stimulus for protein kinase activation, including the mitogen activated protein kinase (MAPK; ERK1/2) module. Based on these studies we hypothesized that GIP could regulate cell fate, and sought to examine the underlying mechanisms involved in GIP stimulation of cell survival. GIP potentiated glucose-induced (INS-1)-cell growth to levels comparable to growth hormone (GH) and GLP-1, while promoting cell survival in the face of serum and glucose-deprivation, or treatment with wortmannin or streptozotocin. In the absence of GIP, 50% of cells died after 48 h of serum and glucose withdrawal, whereas 91 ± 10% of cells remained viable in the presence of GIP (n = 3, P < 0.05; EC₅₀ of 1.24 ± 0.48 nM GIP (n = 4)). Effects of GIP on cell survival and inhibition of caspase-3 were mimicked by forskolin, while pharmacological experiments excluded roles for Mek1/2, PI3Kinase, PKA, Epac and Rap 1. Survival effects of GIP were ablated by the inhibitor SB202190, indicating a role for p38 MAPK. Furthermore, caspase-3 activity was also regulated by p38 MAPK, with a lesser role for Mek1/2, based on RNA interference studies. We propose that GIP is able to reverse caspase-3 activation via inhibition of long-term p38 MAPK phosphorylation in response to glucose deprivation (± wortmannin). Intriguingly, these findings contrasted with short-term phosphorylation of MKK3/6p38 MAPKATF-2 by GIP. Thus, these data suggest that GIP is able to regulate INS-1 cell survival by dynamic control of p38 MAPK phosphorylation via cAMP signaling, and lend further support to the notion that GIP regulation of MAPK signaling is critical for its regulation of cell fate.