The pharmacological and medical management of complex chemotherapy regimens are vast and complex, requiring an intimate understanding of physiology, particularly when novel biologic agents are utilized with commonly used regimens. The molecular classification in patients with diffuse large B-cell lymphoma (DLBCL) is multifaceted, particularly with the expansion of novel molecular targets. The pharmacological and medical management of hematologic malignancies with a tendency to have central nervous system (CNS) involvement is complex and requires an understanding of physiology and pharmacology. Many chemotherapy regimens used to treat hematologic malignancies with either CNS involvement or high risk for CNS disease will include the administration of high dose methotrexate. This requires having physiological understanding with respect to the standard regimens for DLBCL in addition to understanding cytogenetic markers, such as c-myc and bcl-2, the expression of which displays increased likelihood of CNS involvement. In patients with documented CNS disease and active neurological manifestations such as myclonus, headaches, nystagmus, and blurred vision, the utilization of high dose methotrexate has become an essential standard of care. We examine the pharmacologic mechanisms of high dose methotrexate in patients with hematologic malignancies such as DLBCL and review the most common toxicities on a multidisciplinary level.