Lung cancer is the second most common form of cancer in the United States, and although it accounts for 15% of all cancers, it is the most lethal, accounting for approximately 28% of cancer deaths. In 2002, it is estimated that 177,000 new cases of lung cancer will be diagnosed in the United States, and an estimated 160,000 men and women will die from the disease. This mortality rate is greater than that attributable to colorectal, breast, and prostate cancer combined. Systemic treatments for lung cancer with standard chemotherapy agents are still relatively ineffective. Agents targeting novel proliferative and survival pathways in lung cancer are needed to improve treatment outcomes. In recent years, numerous agents inhibiting aberrant processes in tumor cells have undergone clinical evaluation. This review is the second of a two-part series that summarizes pertinent preclinical and clinical information on novel drugs that target critical abnormalities in lung cancer. In this article, agents that were developed to inhibit various aspects of tumor protein trafficking and protein degradation, cell cycle regulation, angiogenesis, and antigenicity are described. Future approaches to treatment are suggested.