Performance enhancement of structural materials in extreme radiation environments has been actively investigated for many decades. Traditional alloys, such as steel, brass and aluminum alloys, normally contain one or two principal element(s) with a low concentration of other elementals. While these exist in either a mixture of metallic phases (multiple phases) or solid solution (single phase), limited or localized chemical disorder is a common characteristic of the main matrix. In sharp contrast to the traditional alloys, recently developed single-phase concentrated solid so lution alloys (CSAs) contain multiple elemental species in equiatomic or high concentrations with different elements randomly arranged on a crystalline lattice. Due to the lack of elemental predictability in these CSAs, they exhibit significant chemical disorders and unique site-to-site lattice distortions. While it has long been recognized that specific compositions of traditional alloys have enhanced radiation resistance, it remains unclear how the atomic-level heterogeneity affects defect formation, damage accumulation, and microstructural evolution. Such knowledge gaps have been a roadblock to future-generation energy technology. CSAs with a simple crystal structure, but complex chemical disorder are ideal systems to understand how compositional complexity influences defect dynamics, and to fill the knowledge gaps with focus on electronic-and atomic-level interactions, mass and energy transfer processes, and radiation resistance performance. Recent advances of defect dynamics and irradiation performance of CSAs are reviewed, intrinsic chemical effects on radiation performance are discussed, and future directions are suggested.