The recreational use of legal and illegal drugs has significant effects on immune responses and can potentially modulate susceptibility to infection by a number of pathogens. A number of agents including cannabinoids (marijuana), cocaine opiates, amphetamines, nicotine and alcohol were demonstrated to have potentially adverse effects on the susceptibility to infections, mediated most likely, by adverse effects on immunity. As such, these drugs of abuse could have significant and potentially adverse effects on the vaccination efficacy of a number of vaccines currently on the market and on potential experimental vaccines currently in the pipeline. This review will present an overview on how drugs of abuse potentially impacts immune responses and vaccination efficacy. The emphasis of this review will be the effects of opiate abuse, as exemplified by injecting/intravenous drug users (IDU), on HIV/AIDS and its potential impact on vaccine efficacy trials against this devastating infection/syndrome.