Primary effusion lymphoma (PEL) is a very rare subgroup of B-cell lymphomas presenting as pleural, peritoneal and pericardial neoplastic effusions in the absence of a solid tumor mass or recognizable nodal involvement. There is strong evidence that Kaposi's sarcoma-associated herpesvirus (KSHV) is a causal agent of PEL. PEL tumor cells are latently infected by KSHV with consistent expression of several viral proteins and microRNAs that can affect cellular proliferation, differentiation and survival. The most relevant data on pathogenesis and biology of KSHV have been provided by studies on PEL-derived cell lines. Fourteen continuous cell lines have been established from the malignant effusions of patients with AIDS-associated and non-AIDS-associated PEL. These KSHV+ EBV+/- cell lines are well characterized, authenticated and mostly available from public biological resource centers. The PEL cell lines display unique features and are clearly distinct from other lymphoma cell lines. PEL cell lines represent an indispensable tool for the understanding of KSHV biology and its impact on the clinical manifestation of PEL. Studies on PEL cell lines have shown that a number of viral genes, expressed during latency or lytic life cycle, have effects on cell binding, proliferation, angiogenesis and inflammation. Also, PEL cell lines are important model systems for the study of the disorder of PEL including the lack of invasive or destructive growth patterns and the peculiar propensity of PEL to involve body cavity surfaces.