The emergence and rapid spread of extremely multiresistant bacteria necessitates every effort to develop novel antibacterial agents. Host-derived antimicrobial peptides (AMPs) pexiganan (a magainin), omiganan (an indolicidin), and iseganan (a protegrin) have been in clinical phases for more than 10 years and provide little in combating against those bacteria. Even though some recent approaches may yield more effective and better-tolerated derivatives of host-derived AMPs, most novel derivatives suffer from weak activity, nonspecific cytotoxicity, and apparent susceptibility to proteolysis. Few have undergone any systematic toxicity and efficacy studies. Bacterial peptides and their derivatives, such as lantibiotics, the RTA-3 peptide, and novel polymyxins, as well as certain peptidomimetics, such as ceragenins, might be more useful.