Nitric oxide (NO) mediates a large number of physiologic and pathologic functions, yet our understanding of its complex role is incomplete. As a modulator of normal host function, NO regulates vascular tone, platelet and leukocyte function, cell-to-cell communication, neurotransmission and a number of sub-cellular events. Nevertheless, excess NO can be detrimental to the host. This is most evident in the systemic vasodilation observed in endotoxic shock during which NO acts to mediate systemic vascular smooth muscle cell relaxation in response to inflammatory cytokines. The evidence that NO is responsible for the direct negative inotropic effects in the heart seen in sepsis, however, is less convincing. Furthermore, whereas NO production in the vascular wall may be detrimental, transient increases in NO synthesis at other sites can have survival value in sepsis depending in part on the quantity and duration of NO synthesis and the concurrent production of reactive oxygen species. Early clinical studies utilizing non-selective nitric oxide synthase (NOS) inhibitors in sepsis show conflicting results, but provide hope that more specific inducible-NOS inhibitors may have some utility in sepsis.