Synergistic interaction of multiple growth factors (GF) in skin controls the processes that promote skin repair. GFs have been shown to affect different pathways of skin repair and rejuvenation with many GFs working in close cooperation with one another and with other endogenous agents. Intrinsic and extrinsic aging of skin reduces both the levels of natural GFs and the number and activity of fibroblasts. Supplementing skin's endogenous GFs may enhance natural repair processes and accelerate the reversal of damage caused by intrinsic and extrinsic skin aging. In spite of their large molecular weight, evidence suggests that a small fraction of topically applied GFs penetrating into superficial epidermis can elicit a fibroblast-mediated response in the dermis. GF mixture secreted by human fibroblasts grown in conditions resembling the physiological condition of dermis, and present at high concentrations in a stable formula is most likely to provide an ideal cosmeceutical product. This naturally balanced mixture is also likely to contain other important, but as yet unidentified, substances that affect skin healing. Such a complex mixture cannot be reproduced using synthetic substances. Clinical studies have shown that topical application of products containing high concentrations of a physiologically balanced mixture of GF appears to reverse the signs of skin aging. A synergistic combination of antioxidants, matrix building agents and skin conditioners with physiologically balanced GF provides a novel and comprehensive paradigm of skin rejuvenation.