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 see3). 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 of fully labelled 13C Lysine SILAC mice to screen skeletal muscle for myokine candidates. After fractionation and digestion of skeletal muscle samples, the resultant peptides were analysed by LC-MS/MS. In 10 fractions we identified 2280 proteins with a peptide false discovery rate of 5%. 593 of these proteins were quantified across exercise and control experiments, 337 of which contained at least two SILAC ratios. Enrichment of the data set for the gene ontology cellular component, extracellular region or space, distinguished a selection of candidate myokines, currently undergoing validation. These candidates will be discussed.