Muscle loss is common during aging and chronic diseases, such as cancer and acquired immunodeficiency syndrome. Moreover, muscle loss has been correlated with decreased physical function, quality of life, and mortality in these populations. Therefore, interventions to counteract muscle loss in the elderly and clinical populations are needed. Recently, the efficacy of the leucine metabolite, β-hydroxy-β-methylbutyrate (HMB), to maintain muscle mass has been investigated in these populations. Many studies have found increases in lean mass and strength in the elderly and clinical populations when using HMB; however, not all studies have found beneficial effects of HMB supplementation. The present review summarizes published human studies investigating the efficacy of HMB supplementation in the elderly and clinical populations. In addition, the mechanisms by which HMB may exert its effects are summarized and future research directions are suggested.