This paper aims to provide a comprehensive review on the physico-chemical factors governing the flotation of Cu-Mo-Fe sulfide ores in seawater, which is different from NaCl or KCl solutions because it contains hydrolysable ions such as Mg²⁺, Ca²⁺, HCO₃^-, CO₃^2-, etc., which can precipitate with lime as hydroxides, Ca, and Mg insoluble salts. Under pH 9.0 Mg²⁺ ions do not depress molybdenite. However, over the critical pH of precipitation of Mg(OH)₂ (pH>10.0), molybdenite is strongly depressed in seawater. This detrimental effect on molybdenite discards the use of lime to depress pyrite in Cu-Mo-Fe ores floated in seawater. In plant practice, the use of sodium metabisulfite (MBS) has replaced lime as a pyrite depressant. It works at pH 6.5-7.0 where the natural floatability of molybdenite is enhanced. Consequently, pH control in rougher and cleaning circuits, and the use of MBS to depress pyrite, have allowed the successful use of non-desalinated seawater in flotation of Cu-Mo-Fe sulfide ores at industrial scale.