Among the numerous alterations in adipose tissue metabolism in obesity is an increased activity of lipoprotein lipase (LPL), the rate-limiting enzyme in triglyceride assimilation. The present paper summarizes a series of experiments demonstrating that the regulation of LPL activity is also impaired in obesity. In normal subjects, glucose intake leads to an increase in adipose tissue LPL activity; this phenomenon can also be demonstrated by incubation of adipose tissue in an insulin-containing buffer in vitro. In contrast, the initially high enzyme activity of adipose tissue from obese subjects is non-responsive to glucose and insulin in vivo and in vitro. However, incubation of adipose tissue from obese subjects in the absence of glucose and insulin led to a rapid decline in enzyme activity and elicited a normal response to subsequent exposure to glucose and insulin. These data indicate that the hyperinsulinemia of the obese tissue donor may be of importance for the abnormalities of LPL activity. However, experiments with VMH-lesioned rats demonstrated that insulin levels and LPL activities could be dissociated. In obese and normal-weight rats, standardized with regard to insulin levels by abolition of endogenous insulin production by streptozotocin treatment and substitution with identical doses of insulin, LPL activities and regulation differed markedly, indicating that factors other than insulin are also involved in the dysregulation of LPL activity in obesity.