Although reduced skeletal muscle mass is a major predictor of impaired physical function and survival, it remains inconsistently diagnosed to a lack of standardized diagnostic approaches that is reflected by the variable combination of body composition indices and cutoffs. In this review, we summarized basic determinants of a normal lean mass (age, gender, fat mass, body region) and demonstrate limitations of different lean mass parameters as indices for skeletal muscle mass. A unique definition of lean mass depletion should be based on an indirect or direct measure of skeletal muscle mass normalized for height (fat-free mass index (FFMI), appendicular or lumbal skeletal muscle index (SMI)) in combination with fat mass. Age-specific reference values for FFMI or SMI are more advantageous because defining lean mass depletion on the basis of total FFMI or appendicular SMI could be misleading in the case of advanced age due to an increased contribution of connective tissue to lean mass. Mathematical modeling of a normal lean mass based on age, gender, fat mass, ethnicity and height can be used in the absence of risk-defined cutoffs to identify skeletal muscle mass depletion. This definition can be applied to identify different clinical phenotypes like sarcopenia, sarcopenic obesity or cachexia.