The Gram-negative pathogen Helicobacter pylori is increasingly more resistant to the three major antibiotics (metronidazole, clarithromycin and amoxicillin) that are most commonly used to treat infection. As a result, there is an increased rate of treatment failure; this translates into an overall higher cost of treatment due to the need for increased length of treatment and/or the requirement for combination or sequential therapy. Given the rise in antibiotic resistance, the complicated treatment regime, and issues related to patient compliance that stem from the duration and complexity of treatment, there is clearly a pressing need for the development of novel therapeutic strategies to combat H. pylori infection. As such, researchers are actively investigating the utility of antimicrobial peptides, small molecule inhibitors and naturopathic therapies. Herein we review and discuss each of these novel approaches as a means to target this important gastric pathogen.