Receptor-interacting protein 140 (RIP140) is best known for its functional role as a wide-spectrum transcriptional co-regulator. It is highly expressed in metabolic tissues including mature adipocyte. In the past decade, molecular biological and biochemical studies revealed extensive and sequential post-translational modifications (PTMs) of RIP140. Some of these PTMs affect RIP140's sub-cellular distribution and biological activities that contribute to the development and progression of metabolic diseases. The biological activity of RIP140 that translocates to the cytoplasm in adipocytes is to regulate glucose uptake, adiponectin secretion and lipolysis. Accumulation of RIP140 in the cytoplasm promotes adipocyte dysfunctions, and provides a biomarker of early stages of metabolic diseases. Administering compounds that reduce cytoplasmic accumulation of RIP140 in high fat diet-fed animals can ameliorate metabolic dysfunctions, manifested in improving insulin sensitivity and adiponectin secretion, and reducing incidences of hepatic steatosis. This review summarizes studies demonstrating RIP140's PTMs and biological activities in the cytoplasm of adipocyte, signaling pathways stimulating these PTMs, and a proof-of-concept that targeting cytoplasmic RIP140 can be an effective strategy in managing metabolic diseases.