Primary central nervous system lymphoma (PCNSL) is a rare and aggressive non-Hodgkin lymphoma that affects the brain, eyes, cerebrospinal fluid (CSF), or spinal cord without systemic involvement. Here, we review the clinical presentation, diagnostic work-up, novel pathophysiologic insights, and treatment of immunocompetent PCNSL patients. Diagnosis of PCNSL requires a high level of suspicion as clinical signs and deficits can vary depending upon the involved CNS compartments. Rapid initiation of therapy is essential for good neurologic recovery and disease control. In general, the prognosis of PCNSL has improved significantly over the past few decades, largely due to the introduction and wide-spread use of high-dose methotrexate (MTX) chemotherapy, considered the backbone of first-line polychemotherapy treatment. Upon completion of MTX-based treatment, a consolidation strategy is often required and can consist of non-myeloablative or myeloablative chemotherapy followed by autologous stem cell transplant, radiation, maintenance therapy, or observation. Unfortunately, relapse is common and 5-year survival rates stand at only 30-40%. Novel insights into the pathophysiology of PCNSL have identified key mechanisms in tumor pathogenesis including activation of the B-cell receptor pathway, a suppressed tumor immune microenvironment, and immune evasion. These insights have led to the identification of novel small molecules and agents targeting these aberrant pathways. Agents such as the Bruton Tyrosine Kinase (BTK) inhibitor ibrutinib or immunomodulatory drugs (IMiDs) like lenalidomide or pomalidomide have shown promising response rates in the clinical trial setting for recurrent/refractory PCNSL and are increasingly being adopted in clinical use.