Substance abusers exert a significant cost burden for employers. Evidence is mounting that worker substance abuse may have its greatest impact on productivity losses including increased absenteeism and short-term disability, higher turnover, and suboptimal performance at work. Full-time workers that reported using illicit drugs or abusing prescribed drugs were more likely to report missing two or more workdays in the past month due to illness or injury and were more likely to have skipped one or more days of work in the past month. But what does one do to address this situation? The response is simple if a worker presents himself acutely intoxicated, but how does one handle off duty or chronic use of potentially impairing substances that may or may not affect job performance and safety? This work reviews the regulatory issues surrounding substance use in the workplace as well as drug and alcohol testing. The text examines the main substances of concern and discusses the literature related to disease based and patient based research considering workplace safety. The monograph ends by describing the evaluation of potentially impaired employees and how to gain objective evidence of their ability to function safely and also how to direct troubled employees toward helpful programs.