Although fibrosis is an essential response to acute cardiac tissue injury, prolonged myofibroblast activation and progressive fibrosis lead to further distortion of tissue architecture and worsened cardiac function. Thus, optimal tissue repair following injury requires tight control over myofibroblast activation. It is now recognized that inflammation plays a critical role in regulating fibrosis. In this review we will highlight how advances in the field of innate immunity have led to a better understanding of the role of inflammation in cardiovascular disease and, in particular, in the regulation of fibrosis. Specifically, we will discuss how the innate immune system recognizes tissue damage in settings of acute injury and chronic cardiovascular disease. We will also review the role of different cell populations in this response, particularly the unique role of different macrophage subsets and mast cells.