Mn+1AXn phases exhibit unique laminated atomic structures that result in properties typical of both ceramics and metals. Due to their unusual characteristics, these materials have been proposed for use in a wide variety of industrial applications, including in nuclear reactors—both fission and fusion systems—where they will be exposed to extreme irradiation conditions and high temperatures. Recently, numerous studies have investigated radiation effects on the Mn+1AXn phases, revealing complex behavior—phase transformations, surface modification, and mechanical property changes—induced by ion or neutron irradiation over a range of temperatures. This review summarizes recent experimental and theoretical work on the response of the Mn+1AXn phases to irradiation and discusses the intrinsic controls on the radiation tolerance of these materials. Based on the review of the present body of work, a comprehensive understanding of the mechanisms of irradiation-induced structural modification and defect evolution in Mn+1AXn phases is developed, as well as proposed strategies for designing novel Mn+1AXn phases with enhanced performance under extreme irradiation conditions.