The incidence of oesophageal adenocarcinoma (OAC) has risen rapidly over the last four decades. Consequently, it has become a frequent cause of cancer related deaths worldwide. Significant tumour heterogeneity at the genomic level and limited knowledge of the genetic drivers of disease progression make effective clinical management of OAC challenging. Genetic alterations underlying the development of OAC from the precursor, Barrett’s oesophagus, are tumour suppressor losses at the early stages followed by oncogenic amplifications at the late stages of disease. In particular, key genetic events in the progression from Barrett’s oesophagus to OAC include SMAD4 tumour suppressor loss (mutated in 13% or loss of function in 34% of OAC cases), and frequent amplification (30% of cases) and overexpression (32% of cases) of the gene encoding the adaptor molecule, GRB7. We demonstrated increased tumourigenic potential of Barrett’s oesophagus cell line, CP-B, following SMAD4 knockdown/knockout in vivo compared to SMAD4 wild-type CP-B cell line, suggesting that SMAD4 loss is a crucial event in OAC tumourigenesis. Further, GRB7 knockdown in OE19 and Eso-26 OAC cell lines (GRB7 amplified within 17q12) significantly inhibited cell proliferation, demonstrating a potential contribution of GRB7 amplification in OAC and identifying a potential new therapeutic target. In summary, the identification of genetic drivers and a deeper understanding of the mechanisms that underlie tumour progression in OAC will lead to the development of better therapeutic strategies.