Hypertrophic scars represent the most common complication of skin injury and are caused by excessive cutaneous wound healing characterized by hypervascularity and pathological deposition of extracellular matrix (ECM) components. To date, the optimal and specific treatment methods for hypertrophic scars have not been available in the clinic. Current paradigm has established fibroblasts and myofibroblasts as pivotal effector cells in the pathophysiology of wound healing. Their biological properties including origin, proliferation, migration, contraction and ECM regulation have profound impacts on the progression and regression of hypertrophic scars. These complex processes are executed and modulated by a signaling network involving a number of growth factors and cytokines. Of particular importance is transforming growth factor-β, platelet-derived growth factor, connective tissue growth factor, epidermal growth factor, and vascular endothelial growth factor. This review article briefly describes the biological functions of fibroblasts and myofibroblasts during hypertrophic scars, and thereafter examines the up-to-date molecular knowledge on the roles of key growth factor pathways in the pathophysiology of hypertrophic scars. Importantly, the therapeutic implications and future challenges of these molecular discoveries are critically discussed in the hope of advancing therapeutic approaches to limit pathological scar formation.