In recent years, infectious diseases have again become a critical threat to global public health largely due to the challenges posed by antimicrobial resistance. Conventional antibiotics have played a crucial role in combating bacterial infections; however, their efficacy is significantly impaired by widespread drug resistance. Natural antimicrobial peptides (AMPs) and their polymeric mimics demonstrate great potential for killing bacteria with low propensity of resistance as they target the microbial membrane rather than a specific molecular target, but they are also toxic to the host eukaryotic cells. To minimize antibiotics systemic spread and the required dose that promote resistance and to advocate practical realization of the promising activity of AMPs and polymers, smart systems to target bacteria are highly sought after. This review presents bacterial recognition by various specific targeting molecules and the delivery systems of active components in supramolecules. Bacteria-induced activations of antimicrobial-based nanoformulations are also included. Recent advances in the bacteria targeting and delivery of synthetic antimicrobial agents may assist in developing new classes of highly selective antimicrobial systems which can improve bactericidal efficacy and greatly minimize the spread of bacterial resistance.