Macrophages comprehend a heterogeneous mononuclear phagocytic population with wide range phenotypes and roles in homeostasis maintenance and diseases, such as infections, autoimmunity and cancer. Technology improvements enable researchers to track different macrophage populations in different tissues and situations and hypothesize on their role in promoting inflammation or stimulating tissue repair. Through innate immune recognition system macrophages can launch several effector artilleries that culminate in the production of various types of inflammatory mediators as cytokines, chemokines, lipid mediators and oxygen reactive species, which in turn, influence the behavior of other cells. Furthermore, macrophages and interacting cells are also susceptible to metabolic changes that ultimately will define the outcome macrophage signaling and its effect in the tissue. Here, we present a concise series of discussions on the role of macrophages, its response to the microenvironment and effects on other cells during tissue injury and repair. Triggering of inflammasome in macrophage activation and function is of special interest in this issue. We will emphasize the role of different macrophage subpopulations and the plasticity of these cells during fibrotic process in different models of diseases.