OBJECTIVE:Native Americans have high rates of drug use and dependence yet little is known concerning its etiology or clinical course. These analyses were conducted to describe the heritability of the use of a variety of illicit drugs, as well as the conditional probability of transitioning from use to dependence for each drug class in a community sample of Native American men and women. METHODS:The sample included 460 participants (190 men and 270 women), recruited through community effort, from eight contiguous Indian reservations in Southern California. Participants were assessed using the Semi-Structured Assessment for the Genetics of Alcoholism. The Semi-Structured Assessment for the Genetics of Alcoholism interview retrospectively asks about the initial use and drug dependence of the following illicit drug classes: marijuana, cocaine, stimulants, sedatives, opiates, hallucinogens, and solvents. Heritability of initial use was determined using SOLAR (http://www.sfbr.org/solar/). RESULTS:Ninety-one percent of this select Indian population had tried at least one of the illicit drug classes. The most commonly tried substance was marijuana (88%), followed by stimulants (60%), cocaine (44%), hallucinogens (34%), and solvents (20%). The heritability of initiation of drug use ranged from 0.14 for cocaine to 0.59 for marijuana. The conditional probability of transition from initiation to drug dependence ranged from 0.66 for stimulants to 0.06 for hallucinogens. CONCLUSIONS:These findings suggest that heritability of the initiation of substance use, in Southwest California Indians, may be similar to other population samples. In this population, however, high rates of dependence on marijuana, opiates, and stimulants are seen once initiation of the use of the substance has occurred.