Impurity profiling has become a critical component in pharmaceutical development to ensure drug safety, efficacy, and regulatory compliance. High-resolution mass spectrometers such as Quadrupole Time-of-Flight (Q-TOF) and Orbitrap have revolutionized impurity identification, characterization, and quantification through accurate mass measurements, structural elucidation, and non-targeted analysis. This review highlights the principles, instrumentation, analytical workflow, advantages, limitations, and current applications of Q-TOF and Orbitrap MS in impurity profiling. Recent trends such as HRMS databases, software-assisted structural prediction, and regulatory expectations are also discussed.