There is convincing evidence that the cross-sectional area, the type of myosin expressed, the potential for oxidative phosphorylation and the number of myonuclei of a skeletal muscle fiber are closely interdependent. Each of these variables, as well as the shape of the fiber, has identifiable physiological consequences. Further, it is suggested that the cytoplasmic to myonucleus ratio is a function of the myosin type and the amount and/or rate of protein synthesis and degradation. Although the neuromuscular activity (electromyographic activity) as well as the associated mechanical and metabolic events have significant regulatory influences on protein metabolism, there are other important regulatory factors independent of these activity-related events. Both the activity and non-activity related regulatory mechanisms probably occur via a cascade of cellular events. The specific combinations of cellular responses that occur may define the nature of the modulatory effects on specific proteins. In spite of the complexity of the regulatory mechanisms of protein modulation and how these responses are structurally integrated into or removed from functional fibers, it is suggested that controlled studies of human neuromuscular function can be more accurately defined and interpreted when fiber and muscle size and shape are considered.