Emerging reports now indicate alterations of arachidonic acid metabolism with carcinogenesis and many COX and LOX inhibitors (used for the treatment of inflammatory diseases) are being investigated as potential anticancer drugs. Results from clinical trials seem to be encouraging but a better knowledge of the dynamic balance that shifts toward lipoxygenases (and different isoforms of LOXs) and cyclooxygenase-2 are essential to progress in the design of new drugs more specially directed on chemoprevention or chemotherapy of human cancers. So, on the basis of these results, it seemed useful to study the advantages of combination of COX inhibitor with LOX inhibitor and a next step will be the conception of dual inhibitors able to induce the anticarcinogenic and/or to inhibit the procarcinogenic enzymes responsible for polyunsaturated fatty acid metabolism. After a rapid summary of some recent reviews published on the involvement of different COX and LOX isoforms present in human cells, we will discuss on cross-talk reported between the downstream pathways which contribute to the development and progression of human cancers. This will lead us to evoke and to justify alternative strategies to develop agents that modulate multiple targets simultaneously with the aim of enhancing efficacy or improving safety relative to drugs that address only a single enzyme.