Published data on hedgehog (Hh) pathway activation in colorectal cancer (CRC) are conflicting, and the effect of the Hh pathway inhibitor on the viability of colon cancer cells is controversial. This article focuses attention on the often-neglected, yet likely, critical role of Indian Hh in the course of colonic tumor progression and hypothesizes that upregulation of Indian Hh expression may offer a novel therapeutic approach against CRC through inducing differentiation of tumor cells and through abrogating the Sonic Hh signaling that drives CRC growth.