Microvascular dysfunction describes a varied set of conditions that includes vessel destruction, abnormal vasoreactivity, in situ thrombosis, and fibrosis, which ultimately results in tissue damage and progressive organ failure. Microvascular dysfunction has a wide array of clinical presentations, ranging from ischemic heart disease to renal failure, stroke, blindness, pulmonary arterial hypertension, and dementia. An intriguing unifying hypothesis suggests that microvascular dysfunction of specific organs is an expression of a systemic illness that worsens with age and is accelerated by vascular risk factors. Studying relationships across a spectrum of microvascular diseases affecting the brain, retina, kidney, lung, and heart may uncover shared pathologic mechanisms that could inform novel treatment strategies. We review the evidence that supports the notion that microvascular dysfunction represents a global pathologic process. Our focus is on studies reporting concomitant microvascular dysfunction of the heart with that of the brain, kidney, retina, and lung.