Lenalidomide is a functional and structural analogue of thalidomide with a relatively benign toxicity profile and pleiotropic anti-tumor activity, exhibiting anti-angiogenic and immunomodulatory effects. Lenalidomide has already been approved for the management of low or intermediate-1 risk myelodysplastic syndrome with chromosome 5q31 deletion and relapsed/refractory multiple myeloma in combination with dexamethasone. During the last five years, multiple clinical trials have been conducted to explore its potential efficacy in hematologic as well as in solid malignancies, revealing a significant benefit in clinical outcomes. This review outlines the mechanisms of action, the toxicity profile and the efficacy of lenalidomide, reviewing the current literature and focusing on the current status of the compound in cancer management. The determination of molecular biomarkers, predictive of clinical response to lenalidomide may reveal a more substantial role of this agent in the treatment of hematologic as well as solid malignancies.