Because inhalant nitrites (commonly known as "poppers") were thought to be rapidly cleared from the body, the lay literature has somewhat downplayed their toxicity. However, scientific reports have documented their immunosuppressive effects in animals, and epidemiological studies have implicated their use with the development of Kaposi's sarcoma (KS) in humans. Because inhalant nitrites are exogenous nitric oxide donors, we hypothesized that these substances of abuse might exert part of their toxicological effects through this biochemical product, which has been shown to alter gene regulation and angiogenesis. In a series of studies, we showed that acute and chronic in vivo exposure to isobutyl nitrite (a representative inhalant nitrite) produced significant tissue-dependent alterations in the expression of a number of cancer- and angiogenesis-related genes in mice. In particular, hepatic mRNA and protein expression of vascular endothelial growth factor (VEGF) was significantly stimulated. The in vivo growth rate of a subcutaneous VEGF-responsive tumor was also shown to be accelerated by inhalant nitrite exposure. Because the development of KS is extensively linked to VEGF and its receptors, the purported link between inhalant nitrites and KS may be explained mechanistically, at least in part, through the stimulation of VEGF expression by these inhalants.