The aims of this study were to examine associations between smoking initiation (five cigarettes lifetime) and lifetime psychopathology, regular smoking by family members, and psychopathology in family members; to describe the degree to which the onset of the disorder precedes or follows smoking initiation; and to examine whether smoking initiators differ as a function of age of smoking onset. Nine hundred and forty-one participants were interviewed at three time points, beginning in high school and most recently at age 24. Lifetime psychiatric diagnoses were obtained at each assessment, as were data regarding smoking initiation. Biological parents and full siblings were interviewed for lifetime psychopathology and regular smoking. Most measures of lifetime psychopathology were associated with smoking initiation. Rates of initiation were especially elevated in participants with multiple disorders. Regular smoking by mother and a sibling (but not father) was associated significantly with smoking initiation, as were two of four measures of psychopathology in relatives. When all significant univariate variables were examined in a single model, drug use disorders, regular smoking by mother, and regular smoking by a sibling remained significantly associated with smoking initiation. Smoking initiation preceded approximately half of the examined diagnostic categories. Eleven variables differentiated early vs. late smoking initiators. Several interactions with gender were found. In every instance, smoking initiation was more strongly associated with the risk factor for young women than for young men. To our knowledge, this is the first time that the relations of psychopathology and familial factors with smoking initiation have been examined simultaneously or in this much detail. Results underscore the potential importance of assessing and treating psychiatric disorders in smoking prevention and cessation efforts.