Chemerin is an adipocyte-secreted protein with autocrine/paracrine roles on adipose development and function as well as endocrine roles in metabolism and immunity. Following prochemerin secretion, protease-mediated generation of chemerin isoforms with a range of biological activities is a key regulatory mechanism controlling local, context-specific chemerin bioactivity. Together, experimental and clinical data indicate that localized and/or circulating chemerin expression and activation are elevated in numerous metabolic and inflammatory diseases including psoriasis, obesity, type 2 diabetes, metabolic syndrome and cardiovascular disease. These elevations are positively correlated with deleterious changes in glucose, lipid, and cytokine homeostasis, and may serve as a link between obesity, inflammation and other metabolic disorders. This review highlights the current state of knowledge regarding chemerin expression, processing, biological function and relevance to human disease, particularly with respect to adipose tissue development, inflammation, glucose homeostasis and cardiovascular disease. Furthermore, it discusses study variability, deficiencies in current measurement, and questions concerning chemerin function in disease, with a special emphasis on techniques and tools used to properly assess chemerin biology. An integration of basic and clinical research is key to understanding how chemerin influences disease pathobiology, and whether modulation of chemerin levels and/or activity may serve as a potential method to prevent and treat metabolic diseases.