Hydrophilic interaction chromatography (HILIC) offers a difference in selectivity as compared to traditional normal phase and reversed-phase liquid chromatography and therefore has great potential for the separation of a variety of pharmaceuticals. This review is devoted to summarizing HILIC coupled to tandem mass spectrometric (MS/MS) methods for the rapid, sensitive and accurate determinations of small molecules employed for supporting drug discovery. The perspectives and challenges on performing HILIC-MS/MS assays are also presented.