Biologic sex and sex steroids are important factors in clinical and experimental stroke and traumatic brain injury (TBI). Laboratory data strongly show that progesterone treatment after TBI reduces edema, improves outcomes, and restores blood-brain barrier function. Clinical studies to date agree with these data, and there are ongoing human trials for progesterone treatment after TBI. Estrogen has accumulated an impressive reputation as a neuroprotectant when evaluated at physiologically relevant doses in laboratory studies of stroke, but translation to patients remains to be shown. The role of androgens in male stroke or TBI is understudied and important to pursue given the epidemiology of stroke and trauma in men. To date, male sex steroids remain largely evaluated at the bench rather than the bedside. This review evaluates key evidence and highlights the importance of the platform on which brain injury occurs (i.e., genetic sex and hormonal modulators).