GPR91 is a recently identified cell membrane receptor for the tricarboxylic acid (TCA)-cycle intermediate succinate and it is highly expressed in various organs including the kidney, liver, and adipose tissue. This novel, unconventional role of succinate (i.e. acting as a signaling molecule) via GPR91 can signal mitochondrial stress, a local mismatch between tissue energy supply and demand, and can activate a hypoxia response independent of the hypoxia inducible factor (HIF). Within the kidney, GPR91 is predominantly localized in the luminal cell membrane of the distal nephron-collecting duct system which is located in the most hypoxic part of the organ. Succinate accumulation and GPR91 signaling in diabetes have been linked to the increased synthesis and release of renin, and the activation of the pathogenic renin-angiotensin system (RAS). GPR91 signaling involves Gi and Gq, activation of MAP kinases ERK1/2 and p38, COX-2, and the generation of prostaglandins (e.g. PGE2) which are highly relevant to the control of renal salt and water transport and blood pressure. In the diabetic kidney, the activation of several pathogenic pathways including RAS/hypoxia/fibrosis mediators (pro)renin, VEGF, TGF-b, MCP-1 are GPR91 dependent. GPR91 deficiency has protective effects in the development of albuminuria in a mouse model of diabetic nephropathy and also reduces blood pressure. Due to its diverse tissue expression, GPR91 may play an important physiological role in many organs as well as in complications of diabetes (e.g. in retina, neurons) and other metabolic diseases.