Melanoma is the most malignant of skin cancers. In the United States the incidence of melanoma is increasing more rapidly than any other cancer. Our recent research efforts focused on the development of novel molecules to control expression of specific genes at the transcriptional level. We are designing and developing libraries of non-peptide, non-oligonucleotide small molecule DNA binders aimed to potently and selectively compete with transcriptional factors for their DNA binding sites, using an innovative modular approach (“LEGO” Block’s Approach). Using this concept we have already designed and synthesized a unique library of DNA binding agents and tested for antitumor effects in the NCI screen of tumor cell lines and identified agent (W631) that blocks Sp1 initiated transcription at a conCentreation of 40 nM. Surprisingly, one other compound, WP760, was repeatedly found to be selectively cytotoxic to melanoma, while showing little or no cytotoxicity to other tumors including breast, lung, brain, colon, and leukemia.