Carnero, Amancio et al. ; © The Author 2015. Carcinogenesis is thought to be a multistep process, with clonal evolution playing a central role in the process. Clonal evolution involves the repeated 'selection and succession' of rare variant cells that acquire a growth advantage over the remaining cell population through the acquisition of 'driver mutations' enabling a selective advantage in a particular micro-environment. Clonal selection is the driving force behind tumorigenesis and possesses three basic requirements: (i) effective competitive proliferation of the variant clone when compared with its neighboring cells, (ii) acquisition of an indefinite capacity for self-renewal, and (iii) establishment of sufficiently high levels of genetic and epigenetic variability to permit the emergence of rare variants. However, several questions regarding the process of clonal evolution remain. Which cellular processes initiate carcinogenesis in the first place? To what extent are environmental carcinogens responsible for the initiation of clonal evolution? What are the roles of genotoxic and non-genotoxic carcinogens in carcinogenesis? ; Ministry of Education, Culture, Sports, Science, and Technology of Japan from Japan Science and Technology Agency and JST, CREST (to H.K.); triennial project grant (Strategic Award) from the National Centre for the Replacement, Refinement and Reduction of animals in research (NC.K500045.1 and G0800697 to H.Y.); ISCIII (Instituto de salud Carlos III) (FIS: PI12/01104 to M.L.); Spanish Ministry of Economy and Competitivity, Plan Nacional de I+D+I 2008-2011, Instituto de Salud Carlos III (Fis: PI12/00137, RTICC: RD12/0036/0028 to A. C.) co-funded by FEDER from Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-6844 and CTS-1848 to A. C.) and Consejeria de Salud of the Junta de Andalucia (PI-0135-2010 and PI-0306-2012 to A. C.); National Institute of Environmental Health Sciences (ES016893 to J.P.W.), Maine Center for Toxicology and Environmental Health (J.P.W.); Fondazione Cariplo (2011-0370 to C.M.); United States National Institute of Health-National Institute of Environmental Health Sciences. Kuwait Institute for the Advancement of Sciences (2011-1302-06 to F. al-M.), Grant University Scheme (RUGs) Ministry Of Education Malaysia (04-02-12-2099RU to R.A.H.), Italian Ministry of University and Research (2009FZZ4XM_002 to A.A), the University of Florence (ex6012 to A.A.), US Public Health Service Grants (RO1 CA92306, RO1 CA92306-S1, RO1 CA113447 to R.R.), Department of Science and Technology, Government of India (SR/FT/LS-063/2008 to N.S.). ; Peer Reviewed