Oxygen reduction reaction (ORR), involving either a two-electron (2e − ) pathway or a four-electron (4e − ) pathway, is an important reaction in energy conversion and storage systems. It is well-known that metal−nitrogen−carbon (M−N−C) catalysts, as emerging state-of-the-art electrocatalysts, are applied to fuel cells via the 4e − pathway (e.g., Fe−N−C) while generating hydrogen peroxide via the 2e − pathway (e.g., Co−N−C). However, the effects of the MN x and C−N species on the catalytic activity of ORR require thorough clarification. Especially, the real active sites of the M− N−C configuration are a long-standing conundrum. In this review, the latest advanced M−N−C catalysts were categorized according to the ORR pathways and MN x moieties. Then, the effects of coordination atoms, N-coordinated structures, and pH on the activity of the M−N−C catalysts were discussed. The detection and quantification of the active sites of M−N−C catalysts by in situ Raman spectroscopy and electrochemical techniques were summarized. Finally, the opportunities and challenges for the M−N−C catalysts with efficient activity were highlighted.