Objectives: The publication of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) by the American Psychiatric Association (APA) represents the culminating point of nearly 10. years of hard work of the appointed task force (DSM-5 committee), in charge of its final elaboration. As part of this committee, the Cultural Issues Work Sub-group devoted nearly 3. years to deliberations on how to include clearly defined cultural factors in different components of the new Manual. This article attempts to outline the process and the main accomplishments of its development. Method: After a historical and critical review of the cultural contents included in the earlier DSM editions, the article then, summarizes the work of the DSM-5 Work Sub-group on Cultural Issues aimed at the materialization of its main objectives. A diagnosis-oriented cultural psychopathology research agenda integrates ethnographic, observational, clinical and epidemiologic approaches, each one providing useful information to crystallize into a comprehensive description of a clinical condition with different levels of impact. The risks of over- and under-pathologization of individual and group behaviors have resulted from not considering the cultural context of such behaviors. Results: The Cultural Issues Work Sub-group led to the inclusion in the DSM-5 Manual, of an introductory chapter or section, the structure and applicability of the Cultural Formulation Interview (CFI) and 12 supplementary modules, the elaboration of three cultural concepts of distress, a glossary and additional material. Furthermore, the article analyzes some pending issues of the Sub-group's work, aspects of some of its formulations in need of improvement, and topics requiring additional further investigation. Conclusion: It is clear that the main achievement has been to insert a clear and relevant reference of an ecumenical enough cultural conception that attempts to take into account all the aspects of psychiatric clinical practice, as well as all types of patients throughout the world. Reflections on the eventual crystallization of such efforts and the progress they could globally lead to are also presented.