Comprehensive two-dimensional gas chromatography (GC×GC) was first introduced nearly two decades ago. Currently, it is one of the most powerful and effective techniques for the characterization and analysis of a variety of complex mixtures. GC×GC is based upon separations utilizing two chromatographic columns of differing selectivity, connected in series through an interface known as the modulator. The main role of the modulator is to trap and/or sample the primary column effluent and periodically inject it into the secondary column. This increasingly popular technique results in an enhanced separation with greatly improved peak capacity. In addition, structured chromatograms are typically generated when compounds belonging to homologous series are present in the sample. However, method optimization in GC×GC can be difficult and time-consuming. This review focuses on the optimization of main operational parameters in GC×GC. Consideration is given to aspects such as stationary phase chemistries, column dimensions, carrier gas flow, temperature programs, modulation and detector settings.