The emergence of infections caused by multi-drug resistant (MDR) pathogens pose a major burden to modern healthcare. Exacerbating this issue is the substantial decline in development of new classes of antibiotics by pharmaceutical companies. This has led to renewed interest in the therapeutic potential of natural anti-infective agents such as host defense peptides (HDPs). The broad antimicrobial and immunomodulatory activities of HDPs and their synthetic derivatives, coupled with the fact that they do not readily induce microbial resistance, makes them extremely valuable leads in the development of new treatment strategies for MDR infections. This review examines our knowledge of the mechanisms behind multi-drug resistance as well as the properties of HDPs and their therapeutic potential, especially in the case of MDR infections. Challenges to their development as new therapeutics are also discussed.