Numerous cross-sectional studies find association between intramyocellular lipid (IMCL) content and insulin resistance (IR). However, less is known concerning the effects of interventions on this association. For instance, the effects on IMCL content by interventions of weight loss and physical activity, classically known to improve IR, have only recently begun to be examined. In a recent study, content of IMCL following bariatric surgery was found to decrease dramatically. The decrease in IMCL content was related to the improvement in IR that occurred following bariatric surgery. Conversely, several studies find that with physical activity, IMCL content typically remains unchanged or increases, even though IR improves. Potential explanations for this difference between weight loss and physical activity are discussed in this article.