The clinical presentation and radiographic appearance of PCNSL differ in immunocompetent and immunocompromised patients and are non-specific for both. A cranial MRI revealing a homogenously enhancing, single lesion in a periventricular location is suggestive of PCNSL in the immunocompetent patient. After neuroimaging suggestive of PCNSL, definitive diagnosis should be established by analysis of CSF, vitreous fluid, or biopsy specimen. Brain biopsy remains the gold standard for PCNSL diagnosis in all patients. At the time of diagnosis, the patient should undergo an extent of disease evaluation as recommended by the International PCNSL Collaborative Group (IPCG). This evaluation includes a physical examination; ophthalmological evaluation with a slit-lamp examination; body CT scans; contrast-enhanced brain MRI; lumbar puncture, if safe; bone marrow biopsy; serum LDH; and HIV serology. Testicular ultrasound, for men, and body FDG-PET should also be considered. Baseline and serial evaluation of cognitive function is critical in this patient population, as both the tumor and anti-tumor therapy are capable of negatively impacting neuropsychological function. Prognostic scoring systems are emerging for the PCNSL patient population.