This article presents a review of medicolegal investigations of drug-related deaths among various Hollywood celebrities and popular music icons. The movie stars included: Marilyn Monroe, River Phoenix, John Belushi, Chris Penn, Heath Ledger and Philip Seymour Hoffman. The musicians are exemplified by Elvis Presley, Janis Joplin, Jimi Hendrix, Keith Moon, Sid Vicious, Kurt Cobain, Amy Winehouse, Michael Jackson, Whitney Houston and Prince. The tragic drug-related death of Anna Nicole Smith, a sex-symbol and Playboy model, is also included. The illicit drugs mainly responsible for the fatalities were heroin and/or cocaine or a mixture of the two narcotics. Some of the celebrity deaths were caused by inappropriate use of prescription medications, mostly combined influences of one or more benzodiazepine together with an opiate or opioid pain medication. Polypharmacy increases the risk of adverse drug events and this sometimes causes a sudden and unexpected death. As tolerance to the pharmacological effects of drugs develop, the amounts taken (the dose) are increased, which enhances the risk of a fatal drug-drug interaction. Ethanol was implicated in some of the celebrity deaths, which underscores the dangers of excessive drinking when taking centrally acting drugs. In the case of Amy Winehouse, a talented jazz singer, she died from acute alcohol poisoning, because ethanol was the only psychoactive drug identified in postmortem blood.