The microcirculation is defined as the smallest vessels where gas and nutrient exchange with tissues takes place. One of its primary functions is to ensure adequate oxygen delivery to meet the oxygen demands of tissue cells. Previous data from clinical and experimental studies and the recent development of new imaging modalities, such as Orthogonal Polarization Spectral videomicroscopy and Sidestream Dark Field imaging, have helped to identify the crucial role that microcirculation plays in sepsis. If not corrected, microcirculatory dysfunction can lead to respiratory distress in tissue cells and subsequent organ failure, even in the absence of global hemodynamic deficiency. In the present review, we will address past and recent developments regarding the role of the microcirculation as an important target in the pathogenesis of sepsis and its progression to multiple organ failure. Accordingly, we identify the microcirculation as an important diagnostic and therapeutic target for treatment in sepsis.