Targeted temperature management (TTM) has become a cornerstone in the treatment of comatose post-cardiac arrest patients over the last two decades. Belief in the efficacy of this intervention for improving neurologically intact survival was based on two trials from 2002, one truly randomized-controlled and one small quasi-randomized trial, without clear confirmation of that finding. Subsequent large randomized trials reported no difference in outcomes between TTM at 33 vs. 36°C and no benefit of TTM at 33°C as compared with fever control alone. Given that these results may help shape post-cardiac arrest patient care, we sought to review the history and rationale as well as trial evidence for TTM, critically review the TTM2 trial, and highlight gaps in knowledge and research needs for the future. Finally, we provide contemporary guidance for the use of TTM in daily clinical practice.