Unilateral, chronic low-frequency electrical stimulation (CLFS) is an experimental model that evokes numerous biochemical and physiological adaptations in skeletal muscle. These occur within a short time frame and are restricted to the stimulated muscle. The humoral effects of whole body exercise are eliminated and the nonstimulated contralateral limb can often be used as a control muscle, if possible effects on the contralateral side are considered. CLFS induces a fast-to-slow transformation of muscle because of alterations in calcium dynamics and myofibrillar proteins, and a white-to-red transformation because of changes in mitochondrial enzymes, myoglobin, and the induction of angiogenesis. These adaptations occur in a coordinated time-dependent manner and result from altered gene expression, including transcriptional and posttranscriptional processes. CLFS techniques have also been applied to myocytes in cell culture, which provide a greater opportunity for the delivery of pharmacological agents or for the application of gene transfer methodologies. Clinical applications of the CLFS technique have been limited, but they have shown potential therapeutic value in patients in whom voluntary muscle contraction is not possible due to debilitating disease and/or injury. Thus the CLFS technique has great value for studying various aspects of muscle adaptation, and its wider scientific application to a variety of neuromuscular-based disorders in humans appears to be warranted.