Although insulin has many effects on metabolism and growth, the term “insulin resistance” is normally used to define the reduced ability of insulin to stimulate glucose uptake into muscle and adipose tissues and/or the reduced ability of insulin to inhibit hepatic glucose output.  Muscle and adipose tissue make up a large proportion of body weight, however muscle has a much larger capacity for glucose utilisation and therefore muscle glucose uptake is considered the major contributor to whole body glucose disposal. Fat accumulation (obesity) is associated with increased ectopic lipid deposition and insulin resistance in muscle and many studies have identified potential mechanism for the reduced effect of insulin on glucose uptake in muscle of obese humans and animals. A significant number of these focus on specific lipid species or humoral factors from other tissues activating serine kinases that interfere with normal insulin signalling. Diaclyglycerols, ceramides, inflammatory factors and reactive oxygen species can all impact on insulin signalling but some studies (in vitro and in vivo) do not show consistent links between reduced insulin-stimulated glucose uptake and reduced insulin signalling or increases in DAG, ceramide or inhibitory signalling systems. The design of studies investigating mechanisms of muscle insulin resistance (genetic or dietary models, cell systems), the type of tests used to assess insulin resistance (GTT, ITT, euglycemic clamp, insulin stimulation) and the timing of investigations (1, 3, 16 weeks of diet, day or night) can all point to different primary mechanisms. Finding functional interventions to improve insulin resistance may require a more quantitative analysis of the contribution of potential mechanisms under physiological conditions rather than trying to find one or two molecular targets to explain all aspects of muscle insulin resistance.