Since the only and the milestone FDA approval of becaplermin gel (RegranexTM, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years ago, no new therapeutic (excluding physical therapies, devices, dressings, anti-microbial agents, or other preventive treatments) for any type of wound healing has advanced to clinical applications. During the same period of time, the FDA has approved additional 250 new drugs for various human tumors, which were famously described as “wounds that do not heal”. Two similar pathological conditions have experienced such a dramatic difference in therapeutics. More surprisingly, few in the wound healing community seem to be alarmed by this mysterious deficit. As it is often said, “damaging is far easier than re-building”. In contrast to the primary duty of a cancer drug to damage a single molecule of the signaling network, a wound healing drug must be able to re-build the multi-level damages in the wound. No known single molecule alone is capable of repairing multi-cell-type and multi-pathway damages all at once. We argue that the previous single molecule-based strategy for developing wound healing therapeutics is profoundly flawed in theory. The future success of effective wound healing therapeutics requires a fundamental change in the paradigm.