The nitro group is considered to be a versatile and unique functional group in medicinal chemistry. Despite a long history of use in therapeutics, the nitro group has toxicity issues and is often categorized as a structural alert or a toxicophore, and evidence related to drugs containing nitro groups is rather contradictory. In general, drugs containing nitro groups have been extensively associated with mutagenicity and genotoxicity. In this context, efforts toward the structure-mutagenicity or structure-genotoxicity relationships have been undertaken. The current Perspective covers various aspects of agents that contain nitro groups, their bioreductive activation mechanisms, their toxicities, and approaches to combat their toxicity issues. In addition, recent advances in the field of anticancer, antitubercular and antiparasitic agents containing nitro groups, along with a patent survey on hypoxia-activated prodrugs containing nitro groups, are also covered.