MiRNAs are a new class of small RNA molecules that regulate gene expression at the post-transcriptional and translational levels. MiRNAs have been implicated in the control of many vital biological processes including development, cell proliferation, differentiation, and apoptosis. A growing number of studies have shown that miRNAs also play an important role in carcinogenesis and other diseases. Among the miRNAs identified, miRNA-21 is dramatically up-regulated in cancer cells of various origins. It regulates a wide range of genes and pathways involved in cancer initiation, transformation, invasion, and metastasis. MiRNA-21 also acts as a pro-survival factor in cardiovascular diseases. Aberrant expression in these diseases makes miRNA-21 a potential marker for disease diagnosis and prognosis. This review highlights the complex roles that miRNA-21 plays in cancer and cardiovascular diseases and its potential clinical applications.