Despite substantial progress in the understanding of the pathogenesis of cancer, the development and implementation of strategies for early cancer detection have lagged behind. Harnessing the immune response to tumor antigens is particularly useful for early detection because the immune response occurs early during tumor development and affords signal amplification with the end product, namely reactive immunoglobulins, being released into the circulation allowing easy access through the blood. This article presents recent developments in autoantibody profiling with a focus on proteomic approaches and applications to lung cancer.