Background and Objectives: Wound healing is a complex process with overlapping phases haemostasis, inflammation, proliferation and maturation/matrix remodeling. Each phase of wound healing requires different management strategies, and inappropriate treatment can delay wound healing. The aim of the present study was to evaluate the efficacy of topical application of calmodulin as a significant augmentation of the granulation tissue production process of wound healing and to express of genes CaMKK2, MaP2K6 and CXCR4 at site of wound defect, that have versatile effects on the body and they belong to Ca/camodulin related genes. Material and Methods: In this study thirty albino male rats, weighting (300-400) gram, aged (6-8) months, will be used under control conditions of temperature, drinking and food consumption according to ethical approval committee of college of dentistry university of Baghdad. Incisional wound of full skin thickness will make on cheek of animal (width 2 cm and depth 0.6 cm) and the animals will divided into two groups, the control group, and experimental group, in control group the wound defect will be treated with local application of1μl of distilled water daily, while the experimental group will be treated with local application of 1μl of calmodulin daily. The rats were sacrificed at 2,4,7 days after surgery (five rats for each period), The gene profile will be analyzed in biopsies of previously injured skin and treated with camodulin compared with the control one. Gene expression for Calcium/Calmodulin- dependent protein kinase 2 (CaMKK2), C-X-C Chemokine receptor 4 (CXCR4) and mitogen activated protein kinase kinase 6 (MAP2K6) will be done for each sample by using real-time quantitative PCR analysis. Results: Histology revealed obvious sequential acceleration of wound healing in the Calmodulin group compared with that of the control one, throughout the experimental period. Improvements were observed with regard to epithelial thickness, inflammatory cell infiltration, and contraction of the wound area. Calmodulin on gene regulation compared to sham therapy in all samples of all three points of wound healing but especially in those samples that were retrieved after 3 days of the wound. These analyzes, which can be confirmed by qRT-PCR, may provide new insight into the molecular mechanisms responsible for the effect of camodulin in wound healing and have shown strong links to previous data in vitro using fibroblasts. Conclusion: Local applications of calmodulin has therapeutic potency to improve wound healing. These agents have potential for future clinical applications.