Tryptamines and phenethylamines are two broad categories of psychoactive substances with a long history of licit and illicit use. Profiles of users of recently emerging tryptamines and phenethylamines are nonexistent, however, since surveillance studies do not query the use of these substances. This manuscript describes the types, modes of administration, onset of use, and context of use of a variety of lesser known tryptamines and phenethylamines among a sample of high-risk youth. Findings are based upon in-depth interviews with 42 youth recruited in public settings in Los Angles during 2005 and 2006 as part of larger study examining health risks associated with injecting ketamine. Youth reported that their use of tryptamines and phenethylamines was infrequent, spontaneous, and predominately occurred at music venues, such as festivals, concerts, or raves. Several purchased a variety of these “research chemicals” from the Internet and used them in private locations. While many described positive experiences, reports of short-term negative health outcomes included nausea, vomiting, diarrhea, disorientations, and frightening hallucinations. These findings, based upon pilot study data, move toward an epidemiology of tryptamine and phenethylamine use among high-risk youth.