High-entropy alloys (HEAs) have transcended the conventional solute-solvent alloy design paradigm and emerged as a promising materials platform to overcome the long-standing strength-ductility tradeoff in metallic materials. However, current studies on the strengthening and toughening of HEAs primarily focus on specific microstructural features or individual strengthening mechanisms, lacking a unified theoretical framework integrating alloy composition design, microstructural regulation, and deformation mechanisms. Based on a series of recent studies conducted by the authors and their collaborators, this study proposes and systematically develops the theory of entropy-enthalpy synergistic strengthening and toughening. This theory postulates that the superior mechanical performance of HEAs originates from their multiscale microstructures and cooperative deformation mechanisms, jointly governed by configurational entropy and chemical enthalpy. Building on this concept, a unified framework linking alloy composition design, microstructure development, deformation response, and strengthening-toughening performance is established. From the perspectives of atomic-scale local chemical ordering, nanoscale coherent precipitation, microscale metastability-induced phase transformation, and multiscale microstructural synergy, the strengthening and toughening mechanisms of HEAs are systematically summarized. Representative examples are further discussed to elucidate the similarities and distinctions between the strengthening-toughening mechanisms of HEAs and conventional alloys, thereby establishing a generalized design model for HEA strengthening and toughening.