Almost 50 years ago Goldstein1 proposed the hypothesis that muscle cells possess a “humoral” component that contributes to the maintenance of glucose homeostasis during exercise. Approximately 15 years ago, we identified skeletal muscle as a cytokine-producing organ, demonstrating that the metabolic and physiologic effects of exercise may be mediated by muscle derived humoral factors (for review see2). We have demonstrated that interleukin-6 (IL-6) was the prototypical “myokine”, up-regulated by muscle contraction and released from contracting skeletal muscle, to play important roles in lipid and glucose metabolism in metabolically active tissues. Other subsequently identified myokines were made serendipitously and the “myokinome” continues to grow (for review see 2,3). It is likely that contracting skeletal muscle produces many unidentified myokines that positively act on the metabolism of other organs, presenting novel targets therapeutics for the treatment of complex metabolic diseases. Accordingly, we have recently adopted the use proteomic screening technologies in an attempt to identify the entire contraction-induced myokinome. We have distinguished a selection of candidate myokines, currently undergoing validation and some of which have led to the development of novel drug candidates in or about to enter Phase I clinical trials. These candidates will be discussed in this lecture.