Cationic and amphiphilic peptides are widely distributed in eukaryotic organisms and constitute a first line of host defense against invading pathogens. Some of these host defense peptides (HDPs) combine specific antibiotic activities with modulation of immune responses. Moreover, they are active against bacteria resistant to conventional antibiotics and show only modest resistance development under in vitro selection pressure. Based on these features, HDPs and particularly defensins are considered a promising source of novel anti-infective agents. This review summarizes the current knowledge about defensins from different kingdoms and discusses their potential for therapeutic application.