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The EPHB4 receptor tyrosine kinase (RTK) has recently emerged as an oncogenic factor in many cancers, including lung cancer. Mutations of <jats:italic>EPHB4<\/jats:italic> in lung cancers have previously been identified, though their significance remains unknown. Here, we report the identification of novel <jats:italic>EPHB4<\/jats:italic> mutations that lead to putative structural alterations as well as increased cellular proliferation and motility. We also conducted a bioinformatic analysis of these mutations to demonstrate that they are mutually exclusive from other common RTK variants in lung cancer, that they correspond to analogous sites of other RTKs\u2019 variations in cancers and that they are predicted to be oncogenic based on biochemical, evolutionary and domain-function constraints. Finally, we show that <jats:italic>EPHB4<\/jats:italic> mutations can induce broad changes in the kinome signature of lung cancer cells. 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