In obesity, there is increased nonadipose tissue as well as increased adiposity. The increase of nonadipose tissue entails an increase in skeletal muscle mass. Recent data indicate that obesity aﬀects not only the quantity, but also the ‘‘quality’’ of skeletalmuscle, and this will be one area of focus for this chapter. One manifestation of a change in the composition of skeletal muscle in obesity is an increased lipid content within and around muscle ﬁbers. How this occurs is an important question. Altered composition of skeletal muscle may arise only as a consequence of having become obese, reﬂecting the general increase in adiposity in multiple organs. Yet, there are data that strongly suggest that changes in the physiology and biochemistry of skeletal muscle in obesity dispose to an accumulation of lipid within muscle. Indeed, these changes in muscle in fuel partitioning of lipid, between oxidation and storage of fat calories, may contribute to the pathogenesis of obesity and precede its development. This hypothesis could be of central importance to our understanding of this chronic disease and therefore will be carefully considered in this chapter.