Previous studies have shown beneficial effects of the corticotropin releasing hormone (CRH) family, including the urocortins (UCN1, UCN2 and UCN3), on pancreatic islets and subsequent glucose homeostasis. However, the physiological relevance of this interaction is not currently understood. CRH and urocortins are also expressed by placenta, so this study investigated whether signalling through CRH receptor 1 or 2 (CRHR1/CRHR2) plays a role in the islet adaptation to pregnancy. Pregnant CD1 mice were chronically administered CRHR antagonists from gestational day 7 by subcutaneous osmotic minipumps. Intraperitoneal glucose tolerance and insulin tolerance tests were performed on gestational day 16 and 18 respectively. Plasma levels of CRH and urocortins were compared between pregnant and non-pregnant mice using ELISAs. Blocking total CRHR signalling during pregnancy resulted in impaired glucose tolerance, significantly 15 minutes post glucose (Control: 13.22 ± 1.08 vs. α-helical CRF9-41: 16.83±1.60 mmol/l; P<0.05; mean±S.E.M.; n= 819). Similarly, impaired glucose tolerance was observed in mice administered the CRHR2 antagonist; Antisauvagine-30 (Control: 13.22±1.08 vs. Antisauvagine-30: 16.63±1.60 mmol/l; P<0.05), but not in animals treated with the CRHR1 antagonist; Antalarmin hydrochloride (Control: 13.22±1.08 vs. Antalarmin hydrochloride: 11.93±1.30 mmol/l; P>0.05). Insulin sensitivity was unaffected by CRHR antagonists (AUC-060 min, control: 372±23; Antisauvagine-30: 347±20; Antalarmin hydrochloride: 368±22; P>0.5; n=719). UCN2 was the only one of the CRH family to display an increase in levels during pregnancy (non-pregnant: 92.87±8.33 vs. pregnant: 178.23±37.46 pmol/l, P<0.001; n=68), whilst CRH, UCN1 and UCN3 levels were unchanged. Blocking CRHR2 signalling during pregnancy impairs glucose tolerance, suggesting an endogenous CRHR2 ligand improves glucose tolerance during pregnancy. This ligand is most likely UCN2 because of the increased levels observed in pregnant mice, suggesting an important and novel role for placental UCN2 in the islet adaptation to pregnancy.