The incidence of peptic ulcer disease (PUD) peaked in the late 19th century while transiting into the 20th century. With entry in the new millennium a significant decrease of PUD has occurred. However, demographic changes with an increasing elderly population associated with multiple comorbidities and polypharmacy became responsible for a persistent high rate of peptic ulcer complications. The acid driven concept of PUD has directed the development of surgical procedures and drugs with an increasing potency in acid suppression. High speed of symptom resolution and rapid ulcer healing was obtained with the introduction of proton pump inhibitors, but cure of PUD has failed. The arrival of <i>Helicobacter pylori</i> has revolutionized the history of PUD which has become a curable disease by successful cure of the infection. However, new challenges have emerged with an increase of treatment failures due to increasing antibiotic resistance of <i>H. pylori</i>. The changing pattern in the prevalence of etiologies other than <i>H. pylori</i> demands for accurate identification of the ulcerogenic cause in the individual patient to allow for proper selection of therapy. Management of peptic ulcer bleeding remains a critical clinical challenge. The chapter of PUD is reduced in size and has become more heterogeneous – but is not closed!