Plasma NEFA are an important energy substrate and, furthermore, play a key role in the induction of insulin resistance in the body. The availability of NEFA is determined predominantly by their mobilization from adipose tissue triacylglycerol stores by the process of lipolysis. Adipose tissue lipolysis in man is regulated by a number of hormonal and paracrine and/or autocrine signals. The main hormonal signals may be represented by catecholamines, insulin, growth hormone, natriuretic peptides and some adipocytokines. The absolute levels and relative importance and contribution of these signals vary in different physiological situations, with diet and physical exercise being the main physiological variables that affect the hormonal signalling. Thus, modulations in hormonal signals induce an increase in NEFA mobilization in the post-absorptive state and during an acute bout of exercise, and suppress NEFA mobilization in the postprandial state. In addition, hormonal regulation is modified by long-term interventions in energy balance, such as dietary restriction and/or physical training, and is disturbed in some pathological states, such as obesity or diabetes. The question that remains is whether disturbances in lipolysis regulation in obese and diabetic subjects may be 'corrected' by the long-term interventions in diet and physical activity.