Abstract This review takes an inclusive approach to microvascular dysfunction in diabetes mellitus and cardiometabolic disease. In virtually every organ, dynamic interactions between the microvasculature and resident tissue elements normally modulate vascular and tissue function in a homeostatic fashion. This regulation is disordered by diabetes mellitus, by hypertension, by obesity, and by dyslipidemia individually (or combined in cardiometabolic disease), with dysfunction serving as an early marker of change. In particular, we suggest that the familiar retinal, renal, and neural complications of diabetes mellitus are late-stage manifestations of microvascular injury that begins years earlier and is often abetted by other cardiometabolic disease elements (eg, hypertension, obesity, dyslipidemia). We focus on evidence that microvascular dysfunction precedes anatomic microvascular disease in these organs as well as in heart, muscle, and brain. We suggest that early on, diabetes mellitus and/or cardiometabolic disease can each cause reversible microvascular injury with accompanying dysfunction, which in time may or may not become irreversible and anatomically identifiable disease (eg, vascular basement membrane thickening, capillary rarefaction, pericyte loss, etc.). Consequences can include the familiar vision loss, renal insufficiency, and neuropathy, but also heart failure, sarcopenia, cognitive impairment, and escalating metabolic dysfunction. Our understanding of normal microvascular function and early dysfunction is rapidly evolving, aided by innovative genetic and imaging tools. This is leading, in tissues like the retina, to testing novel preventive interventions at early, reversible stages of microvascular injury. Great hope lies in the possibility that some of these interventions may develop into effective therapies. Graphical Abstract Graphical Abstract In each of the 6 tissues reviewed, we highlight the reciprocal relationship(s) between the tissue’s somatic cells and the microvasculature serving them. Together these components function as a microvascular unit. Early in their course, diabetes mellitus and cardiometabolic disease disrupt these microvascular units and produce tissue dysfunction. Over time, this disruption leads to common (eg, increased endothelial barrier permeability, pericyte loss, capillary rarefaction, disordered angiogenesis, etc.) as well as tissue-specific (eg, microglia activation in the central nervous system and retina, sympathetic overactivity, and perivascular adipose inflammation in peripheral tissues) microvascular injury responses that are orchestrated by a host of both systemic and local signaling processes.