Skeletal muscle and its microvasculature can exhibit remarkable plasticity in response to decreased functional demand (i.e., muscle disuse). Since the microvascular adaptation to disuse does seem to not depend solely on reduced demand, this review examines the various factors that may be responsible for the observed regression of microvascular structure and function during disuse. There are several animal models of muscle disuse; their common feature is that they are associated with a variety of confounding effects that make the interpretation of the "pure" disuse effect challenging. As well, in clinical studies, the effect of disuse can be difficult to separate from that of various pathologies. Regardless of methodological difficulties, degeneration of the capillary wall, capillary loss, arteriolar remodelling, reduced resting state blood flow, and reduced arteriolar responsiveness to acute vasodilative and vasoconstrictive stimuli have all been observed in disused muscles. The level, and presence/absence of these changes may depend on many factors including the duration of disuse, degree of muscle atrophy, residual muscle activity, microvascular blood flow, release of vasoactive agents from the degenerating muscle, muscle type, and the particular pathology associated with the muscle withering in humans. It is the present challenge to discover the presence/absence of key agents (possibly originating at the interface between the blood stream and the vascular wall, within the extracellular matrix, or the muscle fibres themselves) that alter the intra- and/or inter-cellular signalling to explain the mechanism of adaptation of the microvasculature to skeletal muscle disuse.