Although the advent of trastuzumab heralded the beginning of an era with targeted therapy in oesophago-gastric (OG) cancer, this is only relevant in about 20% of patients with advanced disease. A number of randomised phase III trials evaluating agents inhibiting EGFR, mTOR and VEGF pathways failed to yield any survival benefit. Lack of predictive biomarker to enrich target population may in part contribute to this failure in OG cancer. Despite a general appreciation of the high incidence and lethal nature of this disease, development of novel therapies for patients with OG cancer seems to lag behind other solid tumours. Almost all biological treatments recently in phase III testing in patients with OG cancer—including trastuzumab, bevacizumab, cetuximab, panitumumab, lapatinib, and everolimus—are already licensed in other cancers. One recent exception was ramucirumab, an antibody against VEGFR 2, showed an overall survival advantage over placebo as a single agent in patients with pre-treated advanced OG cancer – a surprising result considering drugs targeting angiogenesis alone such as bevacizumab or aflibercept have never demonstrated single agent survival benefit over standards of care in solid tumours. However, a recent genomic array study in gastric cancers suggested that 37% of gastric cancer showed receptor tyrosine kinase amplification prompting other drug targets to be evaluated. Inhibitors against MET, FGFR and PARP are currently attracting extensive research attention in advanced OG cancer. Most importantly, unlike all the previous agents in phase III studies, OG cancer represent one of their first clinical development areas for many of these new agents, reversing a lack of impetus in drug development in OG cancer, which would no doubt yield benefit for these patients in the future.