Nicotinic acid (niacin), a vitamin of the B complex, is used clinically in high doses to decrease total plasma levels of cholesterol. Interestingly, the total cholesterol levels and low-density lipoprotein (LDL) concentrations decrease, while the high-density lipoprotein (HDL) concentrations increase with nicotinic acid treatment. The cholesterol-lowering effects of nicotinic acid result from inhibition of lipolysis in adipose tissue, which decreases plasma levels of free fatty acid (FFA) (Altschul et al., 1955; Carlson, 1963). In a study of nicotinic acid and myocardial infarction in the Coronary Drug Project (1966-1975), patients receiving 3 g/day nicotinic acid exhibited reduced rates of myocardial infarction (Coronary Drug Project Research Group, 1975). However, an unwanted effect of high doses of nicotinic acid is vasodilatation, occurring mainly in the upper body and face, known as flushing. Recently two receptors for nicotinic acid have been identified as class A G protein-coupled receptors that couple to Gi to inhibit accumulation of cAMP (Offermans, 2006). GPR109A (also known as HM74A in humans and PUMA-G in mice) is a high affinity receptor for nicotinic acid, whereas GPR109B (also known as HM74) is a low affinity receptor for nicotinic acid that is found in humans but not rodents (Wise et al., 2003). GPCR109A is found primarily in adipose tissue and immune cells. Cloned human GPR109A-expressing cell line is made in the Chem-4 host, which supports high levels of recombinant GPR109A expression on the cell surface and contains optimized levels of a recombinant promiscuous G protein to couple the receptor to the calcium signaling pathway. Thus, the cell line is an ideal tool for screening for agonists, antagonists, and modulators at GPR109A.