Collectors play a decisive role in froth flotation by selectively hydrophobizing mineral particles. The new understanding of the molecular design of collectors, their flotation mechanism and green manufacture is reviewed in this paper. The density functional theory (DFT) calculation opens a new avenue for understanding the reactivity of the groups and atoms in a collector molecule, and azolethione surfactants including oxadiazolethione, thiadiazolethione, triazolethione, amino-triazolethione and tetrazolethione, have been designed and developed as collectors. The combination application of the DFT calculation and in situ detection technologies establishes a new platform for flotation fundamental research, and the monomolecular layer of a sulfhydryl collector chemisorbed on chalcopyrite has been observed and measured, and the nature of froth flotation is further understood. The new synthetic technologies for collectors such as xanthates and hydroxamates have been developed to prepare them in near atom economy, which supported their green manufacture and industrial upgrading. The new understanding of flotation collectors will boost their future development.