Despite declining incidence in developed countries, gastric cancer is still the second cause of cancer death worldwide, while proximal gastric cancer is increasing in incidence. Cytotoxic combinations of platinum salts, fluoropyrimidines with or without taxanes or anthracyclines improved response rates but failed to improve the median survival of patients with advanced gastric cancer beyond the 12-month benchmark. Novel rationally designed therapies targeting molecular aberrations which are tumour-specific and pivotal for tumour survival, are urgently needed in order to improve patient outcome. Angiogenic mediators, transmembrane receptors, signal transduction molecules, transcription factors, epigenetic regulators and other biomolecules are among potential targets being modulated by monoclonal antibodies or small molecules in current phase I, II and III clinical trials. To date, only the addition of trastuzumab, an anti-HER2 monoclonal antibody combined with chemotherapy has yielded a clinically meaningful survival improvement in patients with advanced gastric cancer overexpressing HER2.