Background and Objective: Diabetes mellitus (DM) is a prevalent disease, with its prevalence increasing over the past few decades, posing a significant public health challenge. Type 2 diabetes mellitus (T2DM) is a chronic condition characterized by abnormal blood glucose levels due to insulin deficiency or resistance. This review delves into the pharmacogenetic implications of sulfonylurea (SU) therapy, elucidating the impact of genetic variations on SUs response, SU-induced hypoglycemia, and the development of secondary failure to this drug among T2DM patients. Methods: The data was obtained through a search on Pubmed and Google Scholar using the following keywords: ‘Sulfonylurea', ‘Type 2 diabetes mellitus', ‘genetic', ‘polymorphism', ‘SNP', ‘drug response', ‘pharmacogenomics', and “precision medicine". Results: Our analysis suggests that genetic variations could significantly influence the response to SU therapy, the risk of hypoglycemia associated with SUs, and the occurrence of secondary failure. However, this review reveals conflicting outcomes for different genes/variants that may be due to the heterogeneity among previous studies. Conclusions: Translating these findings into clinical practice remains a major challenge, underscoring the critical need for more extensive and standardized research to generate precise data. Such data can then be used to develop precision medicine for T2DM and improving patient outcomes.