The global burden of morbidity and mortality arising from viral infections is high; however, the development of effective therapeutics has been slow. As our understanding of innate immunity has expanded over recent years, knowledge of natural host defenses against viral infections has started to offer potential for novel therapeutic strategies. An area of current research interest is in understanding the roles played by naturally occurring cationic host defense peptides, such as the cathelicidins, in these innate antiviral host defenses across different species. This research also has the potential to inform the design of novel synthetic antiviral peptide analogs and/or provide rationale for therapies aimed at boosting the natural production of these peptides. In this review, we will discuss our knowledge of the antiviral activities of cathelicidins, an important family of cationic host defense peptides, and consider the implications for novel antiviral therapeutic approaches.