Colorectal cancer is a leading cause of cancer-related death in the world and there is an urgent need for new strategies to combat this disease. Findings from several independent laboratories have converged on cGMP signaling as an exciting new therapeutic target, but the mechanisms remain controversial. A key intracellular effector of cGMP is protein kinase G (PKG). This article reviews the scientific literature concerning PKG effects on tumor development and progression, and discusses possible strategies for its exploitation in future cancer therapies. Studies from several independent laboratories have described novel anti-tumor effects of PKG in colon cancer cells that include inhibition of tumor growth and angiogenesis. While more preclinical research is warranted to better understand signaling mechanisms, these properties support the notion that PKG is a novel cancer target.