Considerable research has focused on patterns of substance use initiation among adolescents and for users of selected drugs; however, few data are available for methamphetamine (MA) users. This study describes substance initiation patterns for 352 MA users and assesses predictors of age of MA initiation and its sequencing. Subjects were randomly selected from treatment admissions in a large California county and interviewed using an extensive natural history protocol. Average age of MA initiation was 19 years. Nearly all (95%) had used alcohol, marijuana, and tobacco (average initiation age 13); inhalants, hallucinogens, and crack were also commonly used earlier in the drug sequence than MA. Earlier age of MA initiation was related to race/ethnicity (being non-African-American), younger age of first use of any substance, more types of early criminal behavior, and initiating MA use for sensation-seeking reasons. Following initiation of alcohol, marijuana, and/or tobacco, 27% initiated MA before other illicit drugs, 18% initiated another illicit drug before MA, and 56% initiated two or more other illicit drugs before MA. Later MA order in the initiation sequence was related to ethnicity (being African-American) and initiating MA to substitute for another drug. Results may support targeted prevention efforts and development of more effective interventions.