Strength and ductility are the most fundamental mechanical properties of structural materials. Most metallurgical mechanisms for enhancing strength often sacrifice ductility, referred to as the strength–ductility trade-off. Over the past few decades, a new family of alloys—high-entropy alloys (HEAs) with multi-principal elements, has appeared great potential to overcome the strength–ductility trade-off. Among various HEAs systems, CrFeCoNi-based HEAs with a face-centered cubic (fcc) structure exhibit a great combination of strength, ductility, and toughness via tailoring microstructures. This chapter summarizes recent works on realizing strength–ductility combinations of fcc CrFeCoNi-based HEAs by incorporating multiple strengthening mechanisms, including solid solution strengthening, dislocation strengthening, grain boundary strengthening, and precipitation strengthening, through compositional and microstructural engineering. The abundant plastic deformation mechanisms of fcc HEAs, including slips associated with Shockley partial dislocation and full dislocations, nanotwinning, martensitic phase transformation, deformation-induced amorphization, and dynamically reversible shear transformation, are reviewed. The design strategies of advanced HEAs are also discussed in this chapter, which provides a helpful guideline to explore the enormous number of HEA compositions and their microstructures to realize exceptional strength–ductility combinations.