Circulating microRNAs (miRNAs) function as extracellular communication RNAs that play an important role in cell proliferation and differentiation. MiRNA regulation is essential to many cellular processes, and escape from this regulatory network seems to be a common characteristic of several disease processes and malignant transformations. The interest in circulating miRNAs is due to their central role in regulation of gene expression and the implication of miRNA-specific aberrant expression in the pathogenesis of cancer, cardiac, metabolic, neurologic, and immune-related diseases as well as others. Cancer-associated microRNAs have been detected in serum and plasma and hold promise as minimally invasive cancer biomarkers, potentially for assessing disease characteristics in patients with metastatic disease that is difficult to biopsy. In this chapter we summarize the data related to the action of cellular miRNAs on the onset of various diseases, thus bringing together some of the latest information available on the role of circulating miRNAs. Circulating miRNA profiling could improve the diagnosis of cancer, and could predict outcome for cancer patients, while the profiling of alterations in circulating miRNA that may signal a predisposition to cancer, could also be a therapeutic target in these patients.