In Part 1 of this report, we review data on the effects of estrogen (E), the anti-E tamoxifen (TMX), and testosterone (T) on methamphetamine (METH)-induced neurotoxicity in female and male CD-1 mice. Treatment of gonadectomized females with a physiological regimen of E significantly diminished the amount of striatal dopamine (DA) depletion to METH compared with non-E-treated mice. If these E-treated mice received coadministered TMX, the neuroprotective effects of E were abolished. However, TMX administration to either intact female or male mice appeared to exhibit a neuroprotective effect. Whereas E administration one week before METH treatment serves as a neuroprotectant, reversing the treatment order (METH-->one week-->E) failed to indicate any neurorestorative effects for E. This striatal DA-preserving effect of E was gender specific, because males receiving an identical treatment of E followed by METH failed to show any evidence of neuroprotection, nor did the predominantly male gonadal steroid hormone T afford any neuroprotection in gonadectomized male or female mice. In the second part of the report, we direct our attention toward examining some of the means by which E can exert this neuroprotective effect. The findings that gonadectomized female, but not intact male, mice treated with E show a significant reduction in body temperature can contribute to the gender-specific METH neuroprotection. E also diminishes the initial amounts of DA evoked by METH, as observed when E is co-infused with METH into superfused striatal tissue fragments of gonadectomized female and male mice. By contrast, T tends to increase METH-evoked DA responses. Finally, differences in mRNA levels were obtained between male and female mice treated with METH. Intact female mice tend to show greater levels of striatal glial fibrillary acidic protein and decreased levels of plasminogen activator inhibitor-1 compared with males. Each of these factors, combined with our previous findings that E can inhibit DA transporter function, represent significant events contributing to E/gender-dependent effects on METH neurotoxicity.