Quantitative structure-activity relationship (QSAR) has emerged as a pivotal tool in predicting bioactivity and biological properties, significantly contributing to the drug design and discovery process. Since its establishment, QSAR has played a vital role in the successful design and approval of several drugs, while many others have progressed into advanced stages of clinical trials. This chapter compiles notable success stories showcasing the application of QSAR in developing novel drugs for the central nervous system, including anti-Alzheimer and antimigraine drugs. Additionally, we explore the role of QSAR in discovering new candidates for other therapeutic realms, such as antimicrobial, antiparasitic, and antiviral, as well as its contribution to optimizing new anticancer compounds, thereby influencing their efficacy and safety profiles. Through these diverse cases, this chapter underscores the remarkable versatility of QSAR, emphasizing its pivotal role in the drug discovery process across various therapeutic areas. The discussion encompasses challenges and limitations, offering insights into the potential future directions and advancements in applying QSAR methodologies.