Lung cancer is the major cancer killer worldwide, and 5-yr survival is extremely poor (<or=15%), accentuating the need for more effective therapeutic strategies. Significant advances in lung cancer biology may lead to customised therapy based on targeting specific genes and pathways. The main signalling pathways that could provide roadmaps for therapy include the following: growth promoting pathways (Epidermal Growth Factor Receptor/Ras/PhosphatidylInositol 3-Kinase), growth inhibitory pathways (p53/Rb/P14(ARF), STK11), apoptotic pathways (Bcl-2/Bax/Fas/FasL), DNA repair and immortalisation genes. Epigenetic changes in lung cancer contribute strongly to cell transformation by modifying chromatin structures and the specific expression of genes; these include DNA methylation, histone and chromatin protein modification, and micro-RNA, all of which are responsible for the silencing of tumour suppressor genes while enhancing expression of oncogenes. The genetic and epigenetic pathways involved in lung tumorigenesis differ between smokers and nonsmokers, and are tools for cancer diagnosis, prognosis, clinical follow-up and targeted therapies.