The purpose of this chapter is to highlight the rich tradition of self-experiments (SEs) with psychoactive substances carried out by scientists and therapists for more than a century. Scientifically inspired controlled SEs dominated until the end of the twentieth century, when ethical requirements minimized controlled SEs and “wild” SEs expanded particularly with the emergence of new psychoactive substances. The review focuses on laughing gas (nitrous oxide), cannabis, cocaine, hallucinogens, entactogens, and dissociative hallucinogens. This is due to the fact that substances that induce “complex” effects such as alteration of space/time experience, ego dissolution, and increased feelings and insights (e.g., hallucinogens, entactogens) represent by far the majority of SEs, whereas SEs with substances inducing “simple” effects such as euphoria, anxiolysis, dissociation, or emotional blunting (e.g., cocaine, opioids) are much rarer or even absent (e.g., benzodiazepines). Complex drug effects are much harder to describe, thus allowing SEs to fulfill a more important function. SEs with psychoactive drugs appeared to emerge in the mid-eighteenth century, which triggered a long-standing tradition throughout the nineteenth and early twentieth century. SEs have been de facto performed for a variety of reasons, ranging from establishing scientific knowledge and gaining philosophical insights to compensating for personal deficits. Self-experimenters can be divided into two general types. Besides their scientific intentions, “exploratory” self-experimenters intend to expand awareness and insight, whereas “compensatory” self-experimenters might aim for coping with psychiatric symptoms or personality deficits. Scientific limitations of SEs are obvious when compared to double-blind, randomized, placebo-controlled trials. Whereas the former might lead to more “realistic” detailed description of subjective effects, the latter lead to more solid results in respect to objectively measurable “average” effects. Possible adverse effects of SEs were identified that resulted in loss of scientific objectivity and decreased control over substance use and addiction, development of isolation, problematic group dynamics, and “social autism.”