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Currently, 1.8 million Americans use cocaine, 30% of whom are females. Sex differences in the pattern of cocaine abuse may reside in neuroendocrinological modulations that affect the use of and/or dependence on cocaine. This review discusses sex differences in cocaine‐induced behavioral and molecular alterations in the central nervous system, with emphasis on the role of endocrine responses in the neuronal modulations of this drug. Mechanisms and data supporting the role of the hypothalamic‐gonadal axis in the modulation of cocaine‐induced behavioral and molecular alterations are also provided.