Inflammation is a highly complex cellular surveillance system that is essential for anti-microbial defense and wound healing. The inflammatory process relies on multifaceted coordination among various body systems. Many host cells including leukocytes, fibroblasts, endothelial cells and epithelial cells are involved in the inflammatory process. Cellular receptors, such as Toll-Like-Receptors (TLRs), and cytokine receptors, are responsible for recognizing and processing diverse foreign and host challenges. In addition, they regulate the expression of secondary inflammatory mediators such as cytokines, chemokines, complement proteins, and co-stimulatory molecules. These mediators modulate cellular responses by the activation and recruitment of immune cells mediating host cellular and tissue remodeling. Although inflammation is beneficial for host wound healing and defense toward infection, excessive or altered inflammation often leads to a wide range of tissue injuries and human diseases including cardiovascular diseases, diabetes, and multi-organ failure. This review specifically addresses the contribution of macrophages and fibroblasts to inflammation and tissue injury.