Antimicrobial peptides (AMPs) have emerged as one of several viable options for treatment of infections caused by multidrug-resistant microorganisms, which continue to pose the single greatest public health challenge to humankind. Unlike conventional antibiotics, AMPs affects several key extracellular and intracellular targets in bacteria simultaneously, drastically limiting chances of drug-resistance development. Over the years it has been possible to manipulate their chemical structures to design novel anti-infectives for the treatment of systemic and topical infections based on detailed information generated from structural-activity studies. These novel  synthetic AMPs exhibit   enhanced antimicrobial activity, less cytotoxicity to mammalian cells and enhanced stability to proteases. This review discusses some current developments that have expanded our understanding of their diverse killing mechanisms and shows how this has been employed in the design of AMPs with predictable activity.