The Epstein-Barr virus (EBV) is associated with a variety of human malignancies, including Burkitt's lymphoma, Hodgkin's disease, nasopharyngeal carcinoma and gastric cancers. EBV infection is crucial for the oncogenesis of its host cells. The prerequisite for the establishment of infection is the virus entry. Interactions of viral membrane glycoproteins and host membrane receptors play important roles in the process of virus entry into host cells. Current studies have shown that the main tropism for EBV are B cells and epithelial cells and that EBV is also found in the tumor cells derived from NK/T cells and leiomyosarcoma. However, the process of EBV infecting B cells and epithelial cells significantly differs, relying on heterogenous glycoprotein-receptor interactions. This review focuses on the tropism and molecular mechanism of EBV infection. We systematically summarize the key molecular events that mediate EBV cell tropism and its entry into target cells and provide a comprehensive overview.