Substance use, mainly defined as the consumption of alcohol, tobacco, and illegal drugs, is a major risk factor for disease, disability, and mortality. Alcohol consumption can cause a number of chronic diseases, including several types of cancer, diseases of the gastrointestinal tract, various cardiovascular diseases, alcohol use disorders and infectious diseases, such as tuberculosis and pneumonia. Certain patterns of light moderate drinking, without heavy drinking occasions, may incur a protective effect on ischemic disease categories and diabetes. Finally, alcohol has been established as a causal factor for unintentional and intentional injury. Illegal drug use has been mainly linked to four health outcomes: overdose and other injury, noncommunicable diseases, certain mental disorders, and infectious diseases. In the final section, a comprehensive list of diseases attributable to tobacco smoking is provided, and the most important selected medical conditions are described. These include lung cancer, chronic obstructive pulmonary disease, and ischemic heart disease.