Comprehensive two-dimensional (2D) liquid chromatographic (LC x LC) techniques can be considered innovative methods only recently developed and adopted in many configurations. The revolutionary aspect of comprehensive two-dimensional techniques, with respect to classical multidimensional (MD) chromatography, is that the entire sample is subjected to the 2D advantage. The major benefit is that the separation capacities of each dimension are multiplied, offering a high peak capacity to resolve samples of great complexity. The first part of the present review briefly describes the theoretical and practical aspects related to the development of a multidimensional comprehensive liquid chromatographic method. Applicational experiences in comprehensive liquid chromatography are then described, divided into four groups, according to the HPLC modes used in the two dimensions and to the nature of the samples analyzed.