The transverse tubular (t-)system of skeletal muscle couples sarcolemmal electrical excitation with contraction deep within the fibre. Despite continuity of the t-system lumen with the extracellular fluid (ECF), t-system volume (t-vol) is labile, ranging from <0.5% of fibre volume in resting muscle to as much as 10-15% in glycerol-induced vacuolation in both fast and slow twitch fibres of amphibians and mammals (Krolenko & Lucy, 2001). T-vol changes occur in exercise, pathologies including muscular dystrophy, and following experimental manipulation of extracellular ion concentrations or osmolality. This may contribute to fatigue, rhabdomyolysis, and disruption of excitation-contraction coupling. Yet, the mechanisms that underlie t-vol changes are poorly understood. To address this, a multi-compartment computer model of rat skeletal muscle was developed (Fraser et al., 2011) and shown to reach a unique steady state independent of intracellular or intra-t-system ion concentrations. It was used to define the minimum conditions for t-system stability at rest, and to determine the mechanism of t-vol changes observed in previously published experimental work. Simulations were conducted to define the influence of positive and negative hydrostatic pressures, fixed charges, ionic permeabilities and Na+/K+-ATPase density (N). A general tendency was found for the t-system to swell due to net ionic fluxes from the ECF across the access resistance. A stable t-vol is possible when this ionic influx is offset by a net ionic efflux from the t-system to the cell and thence to the ECF, thereby forming a net ion cycle ECF→t-system→sarcoplasm→ECF that is ultimately dependent on Na+/K+-ATPase activity (Fig 1). Surface and tubular membrane properties that maximise this circuit flux were shown to decrease t-vol; such properties include PNa(t)>PNa(s), PK(t)<PK(s) and Nt<Ns (where P denotes permeability and subscripts t and s denote t-system membrane and sarcolemma respectively). Hydrostatic pressure influences the magnitude of volume changes that result from alterations in this circuit flux, whereas fixed charge in the t-system influences both the magnitude and direction of the circuit flux. Using a parameter set derived, where possible, from literature values, the circuit flux theory of t-vol determination was tested against all available experimental studies (including Rapoport, 1969; Dulhunty, 1982; Usher-Smith et al., 2007), as summarized in Table 2. Although these studies generally measured t-system diameter in several amphibian and mammalian systems, the present model predicted t-vol changes that correlate satisfactorily. This work therefore provides a unifying and robust theoretical framework for understanding the determination of t-system volume.