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although many somatic cell types express insulin receptors, the role of insulin in glucose homeostasis is typified by in- sulin’s direct effects on skeletal muscle, liver, and white adipocytes. these tissues perform distinct roles in metabolic homeostasis, necessitating tissue-specific insulin signal transduction pathways. for example, in skeletal muscle, insulin promotes glucose utilization and storage by increas- ing glucose transport and net glycogen synthesis. in liver, insulin activates glycogen synthesis, increases lipogenic gene expression, and decreases gluconeogenic gene expres- sion. in white adipocyte tissue (wat), insulin suppresses lipolysis and increases glucose transport and lipogenesis. despite these diverse effects, the proximal components in- volved in insulin signal transduction are remarkably similar in all insulin-responsive cells. the diversity of physiological insulin responses in different cell types largely owes to dis- tinct distal effectors. the cell-autonomous effects of insulin in skeletal muscle, liver, and wat, with an emphasis on signal transduction events linked to physiological regula- tion of metabolic fluxes, will be explored in section ii. in addition to these direct effects, insulin also exerts impor- tant indirect effects on target tissues. because of the inte- grated, context-specific nature of these indirect effects, they are difficult to model in cultured cells and are consequently less well understood than direct, cell-autonomous effects of insulin. an example of indirect insulin action is the effect of insulin suppression of wat lipolysis to decrease hepatic acetyl-coa content, in turn allosterically decreasing pyru- vate carboxylase activity. this mechanism, together with suppression of glycerol turnover, enables insulin suppres- sion of wat lipolysis to suppress hepatic gluconeogenesis (684, 903). insulin suppression of glucagon secretion through paracrine signaling in the pancreatic islet and insu- lin action in the central nervous system (cns) represent other important pathways of indirect insulin action. these physiological processes will be examined in section iii. when higher circulating insulin levels are necessary to achieve the integrated glucose-lowering response described above, a subject is considered insulin resistant. a variety of clinical entities–prediabetes, lipodystrophy (642), polycys- tic ovarian syndrome (202), nonalcoholic fatty liver disease (520)–are accompanied by increased fasting plasma insulin concentrations. this increased work load for the endocrine pancreas, and consequent - -cell decompensation, is a major mechanism for the development of overt t2d (380, 389, 750). however, the importance of insulin resistance in the pathogenesis of t2d is highlighted by prospective human studies that have revealed insulin resistance as the best pre- dictor of future t2d diagnosis (481, 884). because insulin action serves different functions in different cell types, insu- lin resistance has diverse functional ramifications in the var- ious insulin target tissues. the cellular and molecular phys- iology of insulin resistance will be explored in section iv, with special attention to specific molecular sites of block- ade, contributions of indirect insulin action, and the pro- posed entity of pathway-selective hepatic insulin resistance, wherein some signaling pathways downstream of the insu- lin receptor appear to retain insulin responsiveness while others manifest insulin resistance (99, 921). having described the phenomenon of insulin resistance in section iv, we proceed to examine its mechanistic basis. mechanisms of insulin resistance are most helpfully catego- rized using the molecular mediators, pathways, and net- works involved. the remainder of this review examines the experimental support for several proposed mechanisms of cellular insulin resistance using this paradigm. several lipid moieties, including diacylglycerol (dag), cer- amides, and acylcarnitines, have been implicated in the pathogenesis of liver and skeletal muscle insulin resistance (127, 561, 724). the mechanistic pathways elucidated, with varying levels of experimental support, largely run parallel to one another such that the involvement of one mediator does not preclude the involvement of another. the putative mediators, pathways, and networks involved in lipid-induced liver and muscle insulin resistance are dis- cussed in section v. a substantial literature describes cellular mechanisms for insulin resistance that are thought to be independent of lipotoxicity. these include endoplasmic reticulum stress and the unfolded protein response (481), reactive oxygen intermediates acting in various subcellular compartments (37), and substrate competition between glucose and fatty acids (397, 677). section vi examines the experimental ev- idence