Despite skeletal muscle's central role in the pathogenesis of sarcopenia, measurement methods remain underinvestigated and inadequately validated. Our review indicates that skeletal muscle (SM) measurement methods quantify different components and properties of muscle, ranging from the atomic to whole-body levels of body composition. Laboratory methods tend to measure whole body SM (e.g., total muscle protein, muscle cell mass, and adipose tissue-free SM components) while epidemiological methods tend to measure regional muscle (e.g., anatomic SM of an extremity). Advances in computerized axial tomography and magnetic resonance imaging methods now allow accurate estimates of whole body and regional SM and promise to finally permit comprehensive in vivo studies of SM biology and methodology. These imaging methods may help to resolve many of the confusing issues that surround the investigation of this major body composition component.