This comprehensive review delves into the intricate interplay between gender/sex and MDMA use, drawing upon recent evidence. It explores how girls, as a means of coping with negative emotions, often resort to drug use, while boys primarily initiate drug use due to peer pressure or sensation-seeking tendencies. Women, frequently having endured traumatic life events, may turn to MDMA as a form of self-medication. Notably, women face an elevated risk of contracting sexually transmitted infections due to their altered mental states and diminished condom use during MDMA consumption. Additionally, females exhibit heightened sensitivity to the subjective effects of MDMA, consistently reporting heightened anxiety, adverse effects, and negative side effects. While women may have a higher susceptibility to hyponatremia, intriguingly, they appear to be less vulnerable to MDMA-induced hyperthermia. Although limited, available data suggest that prenatal MDMA exposure could lead to motor delays in infants, necessitating further research to unravel the potential cognitive effects. Furthermore, MDMA-assisted psychotherapy holds immense promise for addressing post-traumatic stress disorder (PTSD) among female subgroups. These pronounced gender and sex disparities in MDMA use and its effects underscore the pressing need for additional research to develop tailored, effective, and safe treatment approaches that account for these fundamental factors.