Gliomas, that do not respond to alkylating agent chemotherapy, can be made more sensitive to chemotherapy through promotor mediated epigenetic silencing of the MGMT gene. MGMT is one of the important markers in glioblastomas as it not only predicts response to therapy but may also be used as an independent prognostic marker. As such, MGMT is gaining increasing traction in diagnosis, prognostication, and therapeutic decision-making for these highly malignant gliomas. Although, MGMT promotor methylation status is becoming more commonly used in neuro-oncology; this test remains imperfect. Because of its increasing use in clinical practice and research, it is integral that we are aware of its pitfalls and complications. Currently, there are many ways to detect a patient's MGMT promotor methylation status, including: quantitative PCR, methylation-specific PCR, pyrosequencing, real time PCR with high resolution melt, and the infinitum methylation EPIC beadChip. The technical aspects, shortcomings, and optimal approach to interpreting the results of each method will be discussed. Furthermore, given that none of these methods have been prospectively validated, the challenge of equivocal cases will be discussed, and technical and logistic strategies for overcoming these challenges will be proposed. Finally, the difficulty in validating these methods, establishing standardized practice, and considerations of the cost of these competing methods will be explored.