Primary central nervous system lymphomas (PCNSL) are aggressive malignancies that arise in distinct anatomical sites, which display unique structural, biological and immunological conditions. So far, despite recent therapeutic advances, these malignancies exhibit one of the worst prognoses among all non-Hodgkin lymphomas (NHL). For a long time, radiotherapy (RT) has been the standard treatment, producing a response rate of 60-65% and a notable neurological improvement in most cases. However, relapse usually occurred within a few months after RT, with a median survival of 14 months and a 5-year survival of approximately 15-24%. Although the introduction of systemic chemotherapy has consistently improved survival, the prognosis of PCNSL is still dismal, with high rates of local relapse and consequent death. Defining the optimum therapeutic management is difficult because of potential selection biases in large retrospective reviews and the limited number of prospective studies. Although studies published on PCNSL are increasing, several therapeutic questions still remain unanswered after a decade of research.