Ionic liquids (ILs) have emerged as more desirable liquids than conventional solvents for chemistry, material science, engineering and environmental science. The scientific literature reveals an exponential increase in the number of research projects aimed at exploring the chromatographic features of ionic liquids. The review provides sound scientific data to examine the structural characteristics of ionic liquids that make them ideal for use in chromatography. This contribution is distinctive since it integrates the synthesis, benefits, drawbacks, and possible uses of ionic liquids in several chromatographic separation processes. Keeping the cation the same, the introduction of different anions is also possible, and this strategy leads to the synthesis of a series of different ionic liquids with varying properties. A detailed probe is given on the influence of ionic liquid structure and properties on their chromatographic behavior, both as stationary phase and mobile phase and/or mobile phase additives. Ionic liquid based immobilized stationary phases and their analyte retention mechanisms (hydrogen bonding, electrostatic forces of attraction, π-π stacking, ion exchange, and hydrophilic interactions, etc.) are critically discussed. Finally, a thorough analysis of the literature suggests that IL-based stationary phases may undergo multi-mode and more flexible retention mechanisms. Their dual polarity can facilitate interaction with both polar and non-polar compounds. Similarly, using IL as a mobile phase can offer more pragmatic and sustainable options for enantiomer separation.