Circulating cryoglobulins have been reported in association with several acute and chronic viral diseases. In all of the reported cases, the viruses involved have been hepatotropic, lymphocytotropic or both. Among the hypotheses concerning the causes of cryoglobulinemia, two possible pathways have been more frequently debated: an impairment of the macrophagic system of the liver, with the consequent impairment of the clearance of gut antigens and immunoglobulins, as the first ring of a chain of events including the activation of the B cell compartment with increased production (and decreased clearance) of cryoglobulins; and a low-grade malignant lymphomatous process involving rheumatoid factor producing clones. Recent evidence of a close association between hepatitis C virus (HCV) and "essential" mixed cryoglobulinemia has focused the attention of several researchers on the mechanisms by which the virus is capable of causing cryoglobulin synthesis. The open questions include: (1) Why do only a minority of chronically HCV-infected people (mainly "sporadically" infected elderly women) develop a cryoglobulinemic syndrome? (2) What kind of mechanisms can up- or down-regulate cryoglobulin production? (3) Are immunoregulatory mechanisms involved? (4) Is there a connection between HCV infection and the low-grade malignant lymphoma hypothesis identifying cryoglobulinemias as the consequence of the slow proliferation of CD5+ B cells? and (5) Are particular HCV genotypes specifically involved in causing cryoglobulinemias? Several of these questions still remain unanswered. HCV has been detected in the peripheral blood mononuclear cells of both cryoglobulinemic and non-cryoglobulinemic infected subjects; on the other hand, the detection of viral RNA in the bone marrow cells of virtually all cryoglobulinemic patients suggests that this might be related to the pathogenesis of the disease.