Lung cancer remains the leading cause of cancer mortality in the US. For the majority of patients with advanced non-small cell lung cancer, chemotherapy with or without radiation therapy is the mainstay of treatment. Despite the modest improvement in survival for these patients, prognosis remains dismal. However, the expanding knowledge of tumor biology in recent years has resulted in the promising development of a new class of "molecularly targeted" agents, which selectively target cancer cells at the molecular, biochemical, and genetic level, thus minimizing toxic effects on normal tissues. A wide range of molecularly targeted agents are being actively investigated in lung cancer therapy as single agents or in combination with conventional modalities. In this review, we discuss some of the agents furthest along in development: epidermal growth factor receptor inhibitors, anti-angiogenic agents, inhibitors of biologically important enzymes such as matrix metalloproteinases and farnesyltransferase, gene therapy including gene replacement and antisense therapy, and cell cycle disruptors.