Insulin resistance in skeletal muscle is an early event in the development of diabetes with obesity being one of the major contributing factors. Conditioned medium (CM) from differentiated human adipocytes impairs insulin signalling in human skeletal muscle cells. Recent data on adipocyte-induced insulin resistance in skeletal muscle cells describes underlying mechanisms of this process. Skeletal muscle insulin resistance involves multiple pathways and irreversible changes in the expression level of critical proteins. Furthermore, the reversibility of insulin resistance could be demonstrated. Several strategies to combat insulin resistance have been developed. One recent approach to treat obesity and the metabolic syndrome is the use of endocannabinoid receptor antagonists such as rimonabant. These compounds might also reduce insulin resistance in type 2 diabetes with effects on adipose tissue and liver and possibly skeletal muscle.