The production of nitric oxide (NO) and its role in the anti-tumor and anti-microbial effects of rodent macrophages appears well established. In contrast, the circumstances required for its release from human monocytes/macrophages and its potential role in human pathology remain controversial. Evidence to be discussed suggests that NO is a redundant, autotoxic, immunosuppressive, and inefficient mediator of macrophage function. For these reasons, the expression of nitric oxide synthase as a rapid-response, high-output effector pathway may have been evolved out of the human monocyte/macrophage response repertoire or severely restricted in its expression. Hypothetical roles for a modest and circumscribed production of NO by human macrophages are proposed.