The arachidonic acid metabolizing enzymes, cyclooxygenase-2 (COX-2) and 5- lipoxygenase (5-LOX), are both highly expressed during the carcinogenesis in colons. Cigarette smoking promotes these carcinogenic processes at the early stage during adenoma formation. In this article, the involvement of COX-2 and 5-LOX, alongside with the dual COX/5-LOX inhibitors in colorectal cancer development is introduced. The co-regulation of 5-LOX and COX-2 in colon cancer growth and its relationship with cigarette smoke and hyaluronic acid-CD44v6 is also described. It is envisaged that dual inhibition of 5-LOX/COX could be the most promising therapeutic option for the treatment of colorectal cancer in humans.