Fast and efficient separation remains a big challenge in high performance liquid chromatography (HPLC). The need for higher efficiency and resolution in separation is constantly in demand. To achieve that, columns developed are rapidly moving towards having smaller particle sizes and internal diameters (i.d.). However, these parameters will lead to high back-pressure in the system and will burden the pumps of the HPLC instrument. To address this limitation, monolithic columns, especially silica-based monolithic columns have been introduced. These columns are being widely investigated for fast and efficient separation of a wide range of molecules. The present article describes the current methods developed to enhance the column efficiency of particle packed columns and how silica monolithic columns can act as an alternative in overcoming the low permeability of particle packed columns. The fundamental processes behind the fabrication of the monolith including the starting materials and the silica sol-gel process will be discussed. Different monolith derivatization and end-capping processes will be further elaborated and followed by highlights of the performance such monolithic columns in key applications in different fields with various types of matrices.