Lipolysis is an important pathway in maintaining energy homeostasis through the degradation of triglycerides in adipose tissue and the release of fatty acids into the circulation as an energy source. However, an elevated level of circulating fatty acids leads to unfavorable metabolic effects such as insulin resistance and dyslipidemia. Cell surface receptors and intracellular components of the lipolytic pathway have been targeted to develop antilipolytic agents, among which are G-protein-coupled receptor agonists and lipase inhibitors. In addition, molecules that stimulate lipolysis have been tested in clinical trials as a treatment for obesity. Together, these molecules represent a diverse group of regulators for this pathway. This review will discuss strategies to target lipolysis and the major issues with representative small-molecule modulators of this pathway.