Due to the rapid emergence of resistant microbes to the currently available antibiotics, cationic antimicrobial peptides have attracted considerable interest as a possible new generation of anti-infective compounds. However, low cost development for therapeutic or industrial purposes requires, among other properties, that the peptides will be small and with simple structure. Therefore, considerable research has been devoted to optimizing peptide length combined with a simple design. This review focuses on the similarities and differences in the mode of action and target cell specificity of two families of small peptides: the naturally occurring temporins from the skin of amphibia and the engineered ultrashort lipopeptides. We will also discuss the finding that acylation of cationic peptides results in molecules with a more potent spectrum of activity and a higher resistance to proteolytic degradation. Conjugation of fatty acids to linear native peptide sequences is a powerful strategy to engineer novel successful anti-infective drugs.