Gastric cancer is the second leading cancer cause of death globally. Apart from the successful targeting of HER2 over-expression in gastric cancer (GC) with trastuzumab, other targeted therapies in GC have fallen short or still in early clinical development. While HER2 over-expression accounts for up to 20% of GC, other potential actionable driver mutations occur at a much lower frequency in GC. In this review we describe some of the more interesting genetic aberrations including driver mutations in gastric cancer that have very potent inhibitors against them already in clinical development. Part I of this review will concentrate on the receptor tyrosine kinase (RTK) gene amplification (HER2, FGFR2, MET, EGFR). Part II will concentrate on gene mutations (HER2, KRAS, PIK3CA, BRAF) and gene rearrangement (ROS1, BRAF, HER2). Because of the low frequency of these potential driver mutations, perseverance in screening for these mutations will be needed in order to enroll enough of each uniquely molecularly defined subset of GC in order to demonstrate significant clinical benefit in a unique molecularly targeted therapy trial. This approach has been successfully employed in the clinical approval of crizotinib for the treatment of ALK-rearranged non-small cell lung cancer. Finally, we discuss a paradigm shift in the personalized treatment of GC patients where multiplex comprehensive screening of all GC patients for all these potential driver mutations simultaneously is performed to achieve efficiencies and timeliness in diagnosis and allowing enrollment into different molecularly targeted therapy trials and the prospective discovery of novel yet unknown actionable driver mutations.