Thalidomide is an old well-known drug firstly used as morning sickness relief in pregnant women and then withdrawn from market due to its severe side effects on fetal normal development. More recently, however, further surveys renewed the interest on this drug. The reason lies in its efficacy in many important disorders including multiple myeloma, breast cancer, and HIV-related diseases. It became clearer that thalidomide exerts multifaceted properties, directing the efforts of many research groups toward the synthesis of several derivatives and the study of their effects, mostly as new anticancer agents. A recent work on thalidomide correlated compounds demonstrated that they are very effective in inducing cancer cells death by triggering TNFα-mediated apoptosis. The most active compounds, bearing a phthalimido moiety in their structure, were able, as well, to reduce drastically the migration of breast cancer cells, through the regulation of two proteins involved in epithelial-mesenchymal transition (EMT), vimentin and E-cadherin. Based on these interesting results, a small library of phthalimide derivatives were synthesized and studied for their antitumor activity on breast cancer cells, particularly on the estrogen-positive (ER+) MCF-7 and the triple negative MDA-MB-231 cells. In this study we report the interesting preliminary results of these compounds as potential new anti-breast cancer agents.