The luteinizing hormone (LH) receptor is fundamental for the regulation of the corpus luteum (CL) in women and non-human primates. Its ligands, LH and human chorionic gonadotropin (hCG), have key roles in the regulation of tissue and vascular remodeling associated with luteal formation and regression. However this remodeling involves the regulation of cells that do not express LH receptors including endothelial cells, pericytes, fibroblasts and macrophages. We have taken a candidate molecule approach to identify important LH/hCG-regulated paracrine molecules and their receptors in CL and assess the effects of their manipulation in vivo and in vitro. Vascular endothelial growth factor (VEGF) acts on endothelial cells and is a major paracrine regulator of luteal angiogenesis and vasculature maintenance. Luteolysis is associated with increased SLIT/ROBO, connective tissue growth factor (CTGF) and matrix metalloproteinase (MMP) expression in luteal fibroblasts. Investigation of the inhibition of these changes by hCG has identified activin A as a novel paracrine luteolysin and locally generated cortisol as a novel paracrine luteotropin. The molecular regulation of luteal function in the primate is complex and the paracrine regulation of luteal function is still not fully understood. Locally, the luteolytic activities of SLIT/ROBO and activin-A are inhibited by hCG and the luteotropic activities of VEGF and cortisol are stimulated by hCG.