White adipose tissue has traditionally been regarded as an organ of energy storage and mobilization. However, it is now recognized that this tissue is also an active endocrine organ that secretes a variety of signaling molecules termed adipokines. These adipokines have diverse autocrine-, paracrine-, and endocrine-like actions that impact a variety of biological and physiological processes, including adipocyte differentiation, local and systemic inflammation, overall energy balance, blood pressure, and glucose and lipid metabolism. Given the regulatory influence on these critical functions, dysregulation of adipokine secretion is believed to be a major contributor to obesity-related disorders such as hypertension, diabetes, and cardiovascular disease. Chemerin is a small, secreted protein that has been reported to serve as a chemoattractant for cells of the immune system such as macrophages and immature dendritic cells that express the cognate receptor chemokine-like receptor-1 (CMKLR1). Using adenoviral- delivered, short hairpin RNAs (shRNAs) to suppress chemerin or CMKLR1 expression, we have demonstrated a novel role for chemerin/CMKLR1 signaling as a positive regulator of adipocyte differentiation and metabolic function in the 3T3-L1 model of adipogenesis. This experimental approach provides an efficient and powerful means to characterize the functional roles of genes known to be involved in adipocyte formation and metabolism as well as to identify novel roles for genes in this model and/or other cells.