Non-small-cell lung cancer is the leading cause of cancer-related death in men and women. Because of its frequent presentation as advanced disease, most non-small-cell lung cancers are treated with palliative systemic therapy. Multiple trials have established the benefit of chemotherapy for palliation and disease control. Of the patients treated with first-line therapy, approximately 30%-40% will subsequently be candidates for second-line treatment. In the past year, pemetrexed and erlotinib have joined docetaxel as the only Food and Drug Administration-approved second-line therapies. Recent phase III trials have also evaluated the use of oral topotecan, polyglutamated paclitaxel, and gefitinib in this setting. In addition, multiple novel agents, including bortezomib, cetuximab, and bevacizumab, are being investigated as single agents or in combination with approved second-line therapies. With the increasing number of therapeutic options for this patient population, patient characteristics and side effect profiles are influencing the therapeutic choices made by physicians. The use of molecular markers to assist in therapeutic decision-making has yet to come to fruition. Research efforts continue to focus on identifying molecular markers and corresponding clinical features that will allow physicians to individualize patients' therapy.