Several genetic and environmental factors increase gastric cancer (GC) risk, with Helicobacter pylori being the main environmental agent. GC is thought to emerge through a sequence of morphological changes that have been elucidated on the molecular level. New technologies have shed light onto pathways that are altered in GC, involving mutational and epigenetic changes and altered signaling pathways. Using various new model systems and innovative approaches, the relevance of such alterations for the emergence and progression of GC has been validated.