The emergence of Multi-Drug-Resistant (MDR) organisms has become a major worldwide clinical problem. The extensive and routine use of the first-line antibiotics to control infections imposed the development of multiple mechanisms of microbial resistance. Despite the fact that numerous advanced technologies enable the molecular design of new antibiotics, the MDR-associated infections remain a great challenge to modern medicine. Consequently, there is an urgent need to find other methods for reducing the antimicrobial resistance problem. Innovative bioinorganic antimicrobial platforms offer an interesting alternative for combating the microbial resistance. Herein, we describe the bioinorganic strategies with multiple mechanisms of action based on i) small metal complexes, ii) metal modified macromolecules, iii) metal and metal oxides nanoparticles, iv) light-activated bioinorganic platforms, to overcome the pathogen's resistance.