Lung cancer is the leading cause of cancer-related deaths. Approximately 29% of all cancer deaths are due to lung cancer, compared to colon - (9%), breast - (7%), ovarian - (3%), stomach - (2%), and bladder cancer - (2%). The incidence of p53 mutations is highest in lung cancer among all cancer types at up to 70%.  In addition, 24-70% of lung cancers have MDM2 over-expression. Approximately 90% of the p53 mutations are missense mutations, most of which are oncogenic gain of function (GOF) mutations. These findings strongly suggest an active role for GOF mutants of p53 and MDM2 overexpression in the etiology and progression of lung cancer. EGFR, mutant p53, and MDM2 play an important role in lung cancer progression inducing invasion, metastasis, and angiogenesis through CXC chemokines. These connections point to an integrated network of events. This review proposes to elucidate the role of p53 mutations, MDM2 overexpression, EGFR and chemokines in lung oncogenesis.