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The Global Burden of Disease study 2010 (GBD 2010) estimated regional and global burden of 291 diseases and 67 risk factors. Here, we provide an overview of the methodological approach taken to this work, as well as the challenges and limitations encountered in deriving the burden of mental and drug use disorders.GBD 2010 estimated the burden of 11 mental disorders and four drug use disorders for 21 regions. This involved a systematic literature search for epidemiological data; setting lay case definitions; synthesizing available epidemiological data into an internally consistent disease model; and quantifying the associated disability and health outcomes, to derive region, sex, year and age-specific burden estimates. Notable challenges included the difficulty in deriving culturally comparable case definitions for mental and drug use disorders, the paucity of epidemiological data and the difficulty in capturing disability associated with mental and drug use disorders.GBD 2010 findings demonstrated the major public health importance of mental and drug use disorders. The methodology used to estimate burden was more sophisticated than previous GBD studies, with some restrictions required in order to achieve defensible numerical measures of burden for mental and drug use disorders.