In discussion of the physiological mechanisms that regulate fat metabolism, and with consideration of the metabolic stimuli that modulate substrate metabolism, the issue of how an acute state of negative lipid balance can be maximized is addressed. The regulation of lipolysis by catecholamines and insulin is reviewed, and the mechanisms of fatty acid mobilization and uptake by muscle are also briefly discussed. The implications of substrate availability and the hormonal response during physiological states such as fasting, exercise, and after food intake are also addressed, with particular regard to the influences on fatty acid mobilization and/or oxidation from eliciting these stimuli conjointly. Finally, a brief discussion is given of both the nature of exercise and the exercising individual, and how these factors influence fat metabolism during exercise. It is also a primary thrust of this paper to underline gaps in the existing literature with regard to exercise timing concerning food ingestion for maximizing acute lipid utilization.