Among mammals, every cell has a biological sex, and the sex of an individual pervades its body and brain. In this review, we describe the processes through which mammals become phenotypically male or female by organizational and activational influences of genes and hormones throughout development. We emphasized that the molecular and cellular changes triggered by sex chromosomes and steroid hormones may generate sex differences in overt physiological functions and behavior, but they may alternatively promote end-point convergences between males and females. Clinical and pre-clinical evidences suggest that sex and gender differences modulate drug consumption as well as of the transition towards drug-promoted pathological states such as dependence and addiction. Additionally, sex differences in drug pharmacokinetics and pharmacodynamics will also influence dependence and addiction as well as side effects of drugs. These effects will further interact with socially gendered factors to result in sex differences in the access to, engagement in and efficacy of any therapeutic attempt. Finally, we maintain that ‘sex sameness’ is as important as ‘sex differences’ when building a complete understanding of biology for both males and females and provide a framework with which to classify and guide investigation into the mechanisms mediating sex differences and sex sameness.