While Epstein-Barr virus (EBV) tropism in B cells and nasopharygeal epithelial cells in the normal host has been demonstrated, recently the role of its infection into non-B cell populations has been suggested to play a pivotal role in the pathogenesis of several EBV-related hematological as well as non-hematological diseases. Ectopic EBV infection in T cells or natural killer (NK) cells has been reported in EBV-associated hematological diseases, such as acute fulminant EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and chronic active EBV infection (CAEBV). Recent advances in the analysis of EBV infection in lymphocyte subpopulations have clarified the differential virus-cell interaction within these EBV-related disorders. EBV infection was predominantly found in CD8(+) T-cells from EBV-HLH, and in CD4(+) T-cells or NK cells from CAEBV, while the majority of EBV infected cells were found in B cells from acute infectious mononucleosis (IM). Different virus-cell interactions between acute EBV-HLH and CAEBV have indicated different pathogenic mechanisms against EBV infection between the two EBV-associated diseases, accounting for the difference in clinical manifestations between the two diseases.