Metronidazole is an antibiotic that has been effective against many microaerophilic microorganisms with importance in medicine and animal husbandry. The development of increasing resistance against current treatments by many of these organisms has created an urgent need to establish the molecular bases of resistance, knowledge which will help to develop novel diagnostic methods and identify new therapeutic targets. Significant progress has been made in understanding resistance to this antibiotic in the human pathogens Helicobacter pylori and, to a lesser extent, Campylobacter spp. However, insufficient knowledge of the physiology and genetics of these and other related bacteria has led to investigations based on hypotheses that themselves must be established more thoroughly. This review presents the status of our current knowledge of metronidazole resistance and outlines reasons to explain some of the conflicting evidence and controversy in the interpretation of results in this area.