H. pylori infection is now recognized as causing serious and life threatening disease in 20% to 30% of those infected. Reliable therapy is problematic. This article addresses the current approach to diagnosis and therapy and new considerations regarding whom to treat. The emphasis of the association of the gastric cancer phenotype of H. pylori infection (cagA positive H. pylori corpus gastritis) and protection against gastroesophageal reflux disease is an example of epidemiology without regard to the biology. Improvements in health and diet and an increase in body mass have accompanied the natural loss of H. pylori from the population. The search for virulence factors to help direct therapy to those who would most benefit has, to date, proved fruitless. Whenever H. pylori is diagnosed, it should be treated.