Selective apoptotic antineoplastic drugs (SAANDs) are a new class of compounds intended for the prevention and/or treatment of neoplasia. Exisulind (Aptosyn™) and CP461 inhibit growth and induce apoptosis in a variety of cancer cell lines including colon cancer. These agents achieve this affect in colon tumor cells by a mechanism involving the inhibition of cyclic GMP phosphodiesterases (cGMP PDEs), increased cGMP levels and activation of cGMP-dependent protein kinase G (PKG). Exisulind and CP461 although inhibitors of cGMP PDEs lack cyclooxygenase inhibition activity. The resulting effect of PKG activation includes the involvement of important regulatory proteins in both the Wnt and JNK1 signaling pathways to induce apoptosis in wild type and mutant APC expressing colon tumor cells. This review will succinctly summarize clinical data and preclinical research on SAANDs as they are related to colon cancer.