Microvascular alterations were first described in critically ill patients about 20 years ago. These alterations are characterized by a decrease in vascular density and presence of non-perfused capillaries close to well-perfused vessels. In addition, heterogeneity in microvascular perfusion is a key finding in sepsis. In this narrative review, we report our actual understanding of microvascular alterations, their role in the development of organ dysfunction, and the implications for outcome. Herein, we discuss the state of the potential therapeutic interventions and the potential impact of novel therapies. We also discuss how recent technologic development may affect the evaluation of microvascular perfusion.