The increasing incidence and prevalence of insulin resistance and its associated co-morbidities represents a growing concern to public health policy across developed economies world wide. While the economic and psycho-social implications of insulin resistance and the ultimate development of type II diabetes mellitus are profound, much of this is associated with the increased probability of afflicted individuals for the development of peripheral vascular disease; with the hallmark characteristics of impaired matching of skeletal muscle perfusion with elevated metabolic demand. Two models of insulin resistance are highlighted in this chapter: the fructose-fed rodent model (which develops insulin resistance in the absence of obesity) and the obese Zucker rat (which develops insulin resistance subsequent to a chronic hyperphagia). While this chapter provides an overview of some of the skeletal muscle perfusion impairments associated with insulin resistance and its satellite co-morbidities, it also provides a discussion of key contributing elements to this relative ischemic condition. Specifically, this chapter will discuss the contributions of altered vascular reactivity from the perspective of both dilator and constrictor responses, the impact of insulin resistance on potassium channel function, structural alterations to microvascular networks (microvascular rarefaction), and the impact of insulin resistance on patterns of capillary recruitment. What rapidly becomes apparent is that the profound impact of pathological states such as insulin resistance on skeletal muscle perfusion represents a spatially and temporally distributed outcome with many contributors resulting in an integrated negative outcome.