The emergence of the microbiome as a significant factor influencing health and disease across a number of organ systems has posed a new challenge for those wishing to identify the optimum treatments for Helicobacter pylori infection. This review aims to address some of these questions. There is a specific concern in the clinical setting about a spectrum of sequelae of this ranging from mild gastrointestinal upset to life-threatening conditions, such as pseudomembranous colitis, as well as overweight and obesity. The literature on the changes induced in the gut microbiota related to H. pylori eradication can be best considered as those which study immediate effects, short-term effects, and long-term effects. Immediate effects usually include decreased bacterial diversity, however, the use of probiotics may reduce the magnitude of change. Studies looking at short term change have consistently shown bacterial diversity to be altered three months after eradication therapy. Most of the long-term studies have shown regression to baseline microbiome diversity after one year, however, this may not be the case for quadruple therapies. Other challenges around the development of antibiotic resistance and the effect of proton pump inhibitors are also discussed.