This special issue of Regulatory Toxicology and Pharmacology contains 9 scientific papers from Philip Morris International about the laboratory and 1 about early clinical investigation of a novel 'Tobacco Heating System'. The studies have employed conventional and a wide range of newer 'omics and bioinformatics techniques to seek and explore potential toxic actions of the inhalable vapour it generates. The methods of study and display of results employed are considered to be a valuable guide and model for wider application in other toxicological investigations because they are directed more to proximal causes of effects than to the cruder distal end points revealed by conventional, empirical procedures. As such they should be regarded as a paradigm for the applicability and accuracy of the testing and prediction of toxic risks.