Non-small-cell lung cancer (NSCLC) is not considered to be immunogenic, but it may provide an accessible target for the properly primed immune system. Identifying lung tumor antigens and presenting them in the optimal context may enable the immune system to generate anti-lung tumor effector cells, which are usually absent. Despite encouraging preclinical and Phase I-II data, no specific active cancer vaccine has been approved for NSCLC therapy to date. Patient selection and measurable immune response methodology assessment could explain these negative results. Vaccine therapy has recently been re-emerging as a potential approach. This article discusses the Phase I, II and III trials investigating the most promising vaccines in the treatment of patients affected by any stage of NSCLC, thus providing a perspective on the future of this approach in this setting.