Elucidation of the physiological effects of nitric oxide (NO) has been of significant interest since the discovery in the 1980s that NO is an endogenous mediator of cardiovascular tone. Biomedical research of nitrogen oxides has nearly exclusively involved NO and its oxidative metabolites while reduced species, such as nitroxyl (HNO) and hydroxylamine (NH2OH), were largely ignored in mammalian systems. Recently, however, HNO has been shown to have considerable promise as a treatment of heart failure, thus renewing interest in both the chemistry and pharmacology of HNO. Here, the biological effects of NO and HNO are compared, and the resulting dissimilarities are related to the distinct reactivity of these redox siblings toward biomolecules.