The chemical profiling of illicit drugs is a complex process. The results are affected by many different factors such as sample size, the sample processing conditions, the used analytical technique as well as the statistics that are applied. Within this proof-of-concept study, which was done in cooperation with the German Federal Criminal Police Office (Bundeskriminalamt, BKA), the adaptability of comprehensive two-dimensional (2D) gas chromatography (GCxGC) combined with a pixel-based chemometric data processing method is demonstrated. Samples of heroin and cannabis are extracted and analyzed with GCxGC-TOF-MS (time-of-flight mass spectrometry) and GCxGC-FID (flame ionization detection). The obtained second-order data are then used to identify possible marker compounds for the discrimination of the samples according to their chemical profile. The pixel-based chemometric process includes preprocessing steps (background correction, alignment of chromatograms and normalization) followed by an adaptation of hierarchical clustering to identify chemically similar samples, and finally a subsequent calculation of Fisher criterion based on the found clustering in order to identify promising marker compounds. The results of the pixel-based data analysis are compared to a limited peak-based study for cannabis and to a well-established standard method for the chemical profiling of heroin.