The mitochondrial B-oxidation of long-chain fatty acids is preceded by a transport step involving the sequential action of carnitine palmitoyltransferase I and I1 (CPT I and CPT II), together with a carnitine-acylcarnitine translocase [11. A broad physiological understanding of the CPT system has been available for three decades, yet despite its operation in almost every tissue of the body this complex transport mechanism has proved extremely refractory to analysis at the molecular level. Renewed efforts to break through the impasse have received impetus from several directions. First, although orignally defined in the context of the regulation of hepatic ketogenesis [Z], the inhibitory effect of malonyl-CoA on CPT I now appears to have much broader significance in mammalian physiology, ie it also appears to play a key role in fuel'cross-talk'in non-hepatic tissues such as heart [3], skeletal muscle [4, 5] and the pancreatic B-cell [6, 7]. Secondly, there is growing interest in the pharmaceutical industry to develop CPT inhibitors as potential adjuncts to insulin in the treatment of diabetes mellitus where fatty acid oxidation is excessive and impacts negatively on glucose homoeostasis [8, 9]. Thirdly, inherited defects at the CPT locus, some with serious consequences, are being reported with ever increasing frequency [10,111. However, it is evident that confusion still surrounds the question of whether, in any given case, CPT I or CPT I1 is the affected enzyme and in which tissue (s) the defect manifests itself. Even less is known about the molecular and genetic factors underlying these conditions. For all of these reasons we and others have been engaged in a major effort to define the CPT system more fully in terms of its structure/function/regulatory relationships. Although considerable progress has been made, particularly in the last five years, this has been accompanied by much debate. In addition, some unexpected and intriguing findings have emerged. In the sections that follow, recent developments in each of these areas will be