The present contribution is focused on the on-line combination of high performance liquid chromatography (HPLC), cryogenically modulated comprehensive two-dimensional gas chromatography (GC × GC), and triple quadrupole mass spectrometry (QqQ MS), generating a very powerful unified separation-science tool. The instrument can be used in seven different combinations ranging from one-dimensional HPLC with a photodiode array detector to on-line LC × GC × GC/QqQ MS. The main focus of the present research is directed to the LC-GC × GC/QqQ MS configuration, with its analytical potential shown in a proof-of-principle study involving a very complex sample, namely, coal tar. Specifically, a normal-phase LC process enabled the separation of three classes of coal tar compounds: (1) nonaromatic hydrocarbons; (2) unsaturated compounds (with and without S); (3) oxygenated constituents. The HPLC fractions were transferred to the GC × GC instrument via a syringe-based interface mounted on an autosampler. Each fraction was subjected to a specific programmed temperature vaporizer GC × GC/QqQ MS untargeted or targeted analysis. For example, the coal tar S-containing compounds were pinpointed through multiple-reaction-monitoring analysis, while full-scan information was attained for the oxygenated constituents.