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Introduction: Thalidomide is an old well-known drug firstly used as morning sickness relief in pregnant women and then withdrawn from the market due to its severe side effects on fetal normal development. However, over the last few decades, the interest in this old drug has been renewed because of its efficacy in several important disorders as, for instance, multiple myeloma, breast cancer, and HIV-related diseases due to its antiangiogenic and immunomodulatory properties. Unfortunately, even in these cases, many after effects as deep vein thrombosis, peripheral neuropathy, constipation, somnolence, pyrexia, pain, and teratogenicity have been reported showing the requirement of careful and monitored use. For this reason, research efforts are geared toward the synthesis and optimization of new thalidomide analogues lacking in toxic effects, able to erase these limits and improve the pharmacological profile., Aims: This review aims to examine the state-of-the-art concerning the current studies on thalidomide and its analogues towards cancer diseases focusing the attention on the possible mechanisms of action involved and the lack of toxicity., Conclusion: In the light of the collected data, thalidomide analogues and their ongoing optimization could lead, in the future, to the realization of a promising therapeutic alternative for fighting cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)