Considerable research, ranging from survey to clinical to genetic, has utilized traditional measures of tobacco dependence, such as the Fagerstrom Test of Nicotine Dependence (FTND) and the Diagnostic and Statistical Manual (4th ed.) (DSM-IV) criteria, that focus on endpoint definitions of tobacco dependence such as heavy smoking, time to first cigarette in the morning, and smoking despite consequences. In an effort to better understand possible theories and mechanisms underlying tobacco dependence, which could be used to improve treatment and research, two multidimensional measures of tobacco dependence have been developed: the Nicotine Dependence Syndrome Scale (NDSS) and the Wisconsin Inventory of Smoking Dependence Motives (WISDM). This research used data from three randomized smoking cessation trials to examine the internal consistency and validity (convergent, concurrent and predictive) of these scales, relative to each other and the traditional measures. Results reveal that NDSS and WISDM subscales are related to important dependence criteria, but in a heterogeneous fashion. The data suggest that there are important underlying mechanisms or motives that are significantly related to different important outcomes, such as withdrawal and cessation. The FTND was most strongly related to abstinence at 1 week and 6 months post-quit, whereas the WISDM Tolerance subscale was most strongly related to abstinence at the end of treatment. The NDSS Priority subscale was consistently predictive of outcome at all three follow-up time points. There is also evidence that WISDM subscales are related to a biomarker of the rate of nicotine metabolism.