Field-effect transistor (FET)-based biosensors not only enable label-free detection by measuring the intrinsic charges of biomolecules, but also offer advantages such as high sensitivity, rapid response, and ease of integration. This enables them to play a significant role in disease diagnosis, point-of-care detection, and drug screening, among other applications. However, when FET sensors detect biomolecules in physiological solutions (such as whole blood, serum, etc.), the charged molecules will be surrounded by oppositely charged ions in the solution. This causes the effective charge carried by the biomolecules to be shielded, thereby significantly weakening their ability to induce charge rearrangement at the sensing interface. Such shielding hinders the change of carriers inside the sensing material, reduces the variation of current between the source and drain electrodes of the FET, and seriously limits the sensitivity and reliability of the device. In this article, we summarize the research progress in overcoming the Debye screening effect in FET-based biosensors over the past decade. Here, we first elucidate the working principles of FET sensors for detecting biomarkers and the mechanism of the Debye screening. Subsequently, we emphasize optimization strategies to overcome the Debye screening effect. Finally, we summarize and provide an outlook on the research on FET biosensors in overcoming the Debye screening effect, hoping to help the development of FET electronic devices with high sensitivity, specificity, and stability. This work is expected to provide new ideas for next-generation biosensing technology.