Adenosine mediates its diverse effects via four subtypes (A₁, A_2A, A_2B and A₃) of G-protein-coupled receptors. The A₁ adenosine receptor (A₁AR) subtype is the most extensively studied and is well characterized in various organ systems. The A₁ARs are highly expressed in adipose tissue, and endogenous adenosine has been shown to tonically activate adipose tissue A₁ARs. Activation of the A₁ARs in adipocytes reduces adenylate cyclase and cAMP content and causes inhibition of lipolysis. The role of A₁ARs in lipolysis has been well characterized by using several selective A₁AR agonists as well as A₁AR knockout mice. However, the contribution of A₁ARs to the regulation of lipolysis in pathological conditions like insulin resistance, diabetes and dyslipidemia, where free fatty acids (FFA) play an important role, has not been well characterized. Pharmacological agents that reduce the release of FFA from adipose tissue and thus the availability of circulating FFA have the potential to be useful for insulin resistance and hyperlipidemia. Toward this goal, several selective and efficacious agonists of the A₁ARs are now available, and some have entered early-phase clinical trials; however, none have received regulatory approval yet. Here we review the existing knowledge on the role of A₁ARs in insulin resistance, diabetes and obesity, and the progress made in the development of A₁AR agonists as antilipolytic agents, including the challenges associated with this approach.