Profiling of impurities in pharmaceutical products is an important part of the pharmaceutical manufacturing process and it is a regulatory expectation. Impurities may influence the safety and efficacy of the pharmaceutical products. Estimation of the impurity of pharmaceuticals provides excellent means for drug authorities to control the manufacturing process. To meet the challenges and to build high degree of purity in drug substances and drug products, it is required to carry out all the investigations for standards of drugs and impurities to get significant results. Different methods are available for impurity profiling; the most common analytical methods are based upon spectroscopic and chromatography separation techniques. One of the powerful tools of impurity profile is liquid chromatography (LC) coupled with mass spectroscopy (MS), and it is employed for the identification of impurities, natural products, drug metabolites, and proteins. LC-MS offers selectivity and specificity in both the chromatographic separation and detection steps, and is found as necessary steps to measure compounds at extremely low concentrations. LC-MS is steadily applied to scrutinize impurity during pharmaceutical product development and manufacturing process to support the safety evaluation of batches used in clinical studies. In this review, strategies for impurity profiling of pharmaceuticals with the applications of LC-MS, LC-MS/MS, LC-ESI/MS and LC-TOF/MS methods will be critically reviewed and discussed.