Severe sepsis and septic shock, which are among the most common causes of death in intensive care units worldwide, cause high morbidity, mortality, and social and economic costs. Therefore, developing successful therapies against sepsis is one of the most important challenges in critical care medicine. Death from septic shock is caused by refractory hypotension and multiple organ failure (MOF). Although excessive systemic vasodilation triggered by nitric oxide (NO) is believed to mediate the hypotension, several endogenous factors and phenomena are responsible for MOF, including tissue hypoperfusion and ischaemia, mitochondrial dysfunction, and other cytotoxic effects, all of which might be directly or indirectly antagonized by local NO. Hence, selective inhibition of the production of hypotension-causing NO in the macrocirculation and/or selective treatment with microvasculature-specific NO donors could theoretically constitute a successful therapy. Recently, the NO metabolite nitrite was recognized as an NO donor specifically in hypoxic/acidic conditions, which can be expected in the septic microvasculature. We recently showed that treatment with nitrite can protect mice against progressive hypothermia, mitochondrial dysfunction, organ damage, and even death induced by tumour necrosis factor or lipopolysaccharide. In this review, we discuss the rationale for using nitrite for the treatment of shock, the possible mechanisms of nitrite-mediated protection, and the lessons that can be drawn for possible future translation of the results from mouse models to the clinic.