The modern monolithic columns emerged more than two decades ago. While the early polymer-based monoliths were used for the rapid separations of proteins, current literature describes a number of different applications in addition to typical liquid chromatography demonstrating versatility of the monoliths. For example, monolithic columns prepared using hypercrosslinking possess a large surface area in numerous mesopores and enable efficient rapid separation of small molecules. New chemistries are being developed to produce monolithic columns for the separation in various chromatographic modes. Modification of pore surface with nanostructures is another recent trend that extends applications of monoliths in the arena of highly selective systems. Recently, a new approach was introduced that enables functionalization of pore surface of monoliths and involves application of metal-organic frameworks (MOFs). These frameworks are compounds consisting of metal ions or clusters coordinated to rigid organic molecules to form one-, two-, or three-dimensional that can be porous. We used two implementations: (i) admixing preformed MOF to the polymerization mixture followed by the thermally initiated free radical polymerization and (ii) forming the MOF within the pores applying layer-by-layer approach. Monoliths also serve as supports for immobilization of enzymes to form very active enzymatic reactors.