To improve the understanding of the mechanisms underlying the behavior of plasma non-esterified fatty acids (NEFA) in the postprandial state, we have developed a physiology-based mathematical model of plasma NEFA dynamics. Known physiological mechanisms are quantified and used to describe NEFA dynamics. Insulin is the major regulator of NEFA metabolism in the postprandial state. Plasma NEFA levels are thus highly dependent on the insulin concentration, the insulin sensitivity of adipose tissue, and the maximal lipolytic rate. In the postabsorptive state, e.g., at low insulin, adipose tissue lipolysis results in a net export of NEFA from adipose tissue to other tissues. Postprandially, the rise in insulin results in: Decreased lipolysis; a higher rate of lipoprotein lipase (LPL) activity; and decreased NEFA uptake and reesterification by adipose tissue stimulation of reesterification. The result is a drop in plasma NEFA after a carbohydrate containing meal. When insulin returns to postabsorptive levels, a rebound in plasma NEFA often occurs. This rebound is due to a restoration of lipolysis, a decrease in NEFA reesterification by adipose tissue and an increased LPL-as insulin activates LPL with a delay of several hours. In conclusion, movements of NEFA depend strongly on insulin-with postprandial plasma NEFA being almost inversely related to the insulin concentration in healthy humans. The model provides an integrative view of NEFA dynamics and a framework for quantitative and conceptual understanding of plasma NEFA fluxes.