Porphyry copper deposits (PCDs) are some of the most important sources of copper (Cu) and molybdenum (Mo). Typically, the separation and recovery of chalcopyrite (CuFeS2) and molybdenite (MoS2), the major Cu and Mo minerals, respectively, in PCDs are achieved by two-step flotation involving (1) bulk flotation to separate Cu–Mo concentrates and tailings (e.g., pyrite, silicate, and aluminosilicate minerals) and (2) Cu–Mo flotation to separate chalcopyrite and molybdenite. In Cu–Mo flotation, chalcopyrite is depressed using Cu depressants, such as NaHS, Na2S, Nokes reagent (P2S5 + NaOH), and NaCN, meaning that it is recovered as tailings, while molybdenite is floated and recovered as froth product. Although conventionally used depressants are effective in the separation of Cu and Mo, they have the potential to emit toxic and deadly gases such as H2S and HCN when operating conditions are not properly controlled. To address these problems caused by the use of conventional depressants, many studies aimed to develop alternative methods of depressing either chalcopyrite or molybdenite. In this review, recent advances in chalcopyrite and molybdenite depressions for Cu–Mo flotation separation are reviewed, including alternative organic and inorganic depressants for Cu or Mo, as well as oxidation-treatment technologies, such as ozone (O3), plasma, hydrogen peroxide (H2O2), and electrolysis, which create hydrophilic coatings on the mineral surface.