The overall survival of gastric cancer patients remains poor despite efforts and advances in its prevention, diagnosis, and treatment. The development of new therapies is crucial for the effective control of this disease. An increasing number of genetic and epigenetic alterations have been associated with distinct histological types of gastric cancer. In this review, we will discuss the involvement of E-cadherin, EGFR, ERBB2, MMR genes, KRAS, and PIK3CA in the development and progression of gastric cancer and their role as biomarkers or as novel putative targets for therapy.