Oxidative stress (OS) arises mainly from exposure to reactive oxygen species (ROS) such as superoxide anion, hydroxyl radical, and hydrogen peroxide. These molecules can cause significant damage to proteins, DNA, and lipids, leading to various diseases. Cells fight ROS with detoxifying enzymes; however, an imbalance can cause damage leading to ischemic conditions, heart disease progression, and neurological disorders such as Alzheimer's disease. Accurate assessment of OS levels is then crucial and oxidized lipidic products are considered relevant OS biomarkers. In fact, lipids are particularly prone to ROS attack, leading to lipid peroxidation, cell membrane damage, and toxic by-products affecting DNA, proteins, and low-density lipoproteins. This review reports on recent advances in LC-MS/MS approaches for OS lipidic biomarkers, focusing on overcoming analytical challenges. 3 different classes of biomarkers have been reported, malondialdehyde, isoprostanes and oxidised sterols. For each class, the main analytical challenges with a particular focus on derivatisation procedure, sensitivity, matrix effect, ionisation have been described and discussed. The recent advancements of the LC-MS-MS procedures move towards simpler approaches, reducing errors and improving the reliability of the measurement thus enabling a comprehensive and robust OS assessment.