In order to demonstrate that Modified Risk Tobacco Products (MRTPs) have the potential to deliver risk reduction when used in place of conventional cigarettes, it is crucial to perform a comprehensive chemical characterization of the aerosols produced by these products. This knowledge will enable a comparison of the different physicochemical properties of aerosol composition, both to optimize our MRTPs and to interpret gene expression results from in vitro and in vivo studies (why and how the different network or pathway perturbations are affected). Orthogonal approaches are used for aerosol characterization and here we report on a fingerprinting method to semi-quantify several hundred aerosol constituents using gas chromatography coupled to high resolution time-of-flight mass spectrometry (GC-HR-TOF-MS) employing isotopic dilution has been developed. This method combines the use of an in-house built chemical master database ‘Unique Compound Structure Database (UCSD)’ with a Quantitative Structure Property Relationship (QSPR) model to build the capability for retention time prediction from the analysis of reference standard compounds for new compound identification. A total of approximately 500 reference standard compounds (including isotopically labeled internal standards) were analyzed by GC-HR-TOF-MS using a DB5-MS GC column while the HR-TOF-MS instrument was operating under electron impact ionization. The electron impact mass spectra of reference compounds were registered in our SpecDb master database (UCSD). Using the prediction model, targeted almost thousand aerosol constituents were identified and categorized into several compound classes according to their physicochemical properties using accelrys pipeline pilot software and used for product comparisons. Semi-quantification was achieved using specific isotopically labeled internal standards representative of each compound class, with the potential of quantifying deliveries of individual aerosol constituents in the region of ng per tobacco product.