Antimicrobial peptides (AMPs) are peptide-based effector molecules produced by the innate immune system to combat microbes. Insects produce the broadest repertoire of AMPs, and their potent antimicrobial activity in vitro and in vivo has promoted their development as alternatives to conventional antibiotics, in an attempt to address the threat of multidrug-resistant pathogens. Here we discuss current obstacles that hinder the therapeutic development of novel insect-derived AMPs, including potential cytotoxic, immunogenic and allergenic side effects, and the high costs of large-scale production. These challenges may be overcome by the falling costs of synthetic peptide analogs and the heterologous production of recombinant peptides in insect cells or plants (molecular pharming). Insect AMPs offer a promising alternative for the treatment of skin, eye and lung infections, and could also restore the susceptibility of multidrug-resistant pathogens to conventional antibiotics when used as combinatorial treatments. Insect AMPs can also be used as templates for the rational design of peptide mimetics to overcome the drawbacks of natural therapeutic peptides.