Cardiac fibroblast activation to hyper-synthetic myofibroblasts following a pathological stimulus or in response to a substrate with increased stiffness may be a key tipping point for the evolution of cardiac fibrosis. Cardiac fibrosis per se is associated with progressive loss of heart pump function and is a primary contributor to heart failure. While TGF-β is a common cytokine stimulus associated with fibroblast activation, a druggable target to quell this driver of fibrosis has remained an elusive therapeutic goal due to its ubiquitous use by different cell types and also in the signaling complexity associated with SMADs and other effector pathways. More recently, mechanical stimulus of fibroblastic cells has been revealed as a major point of activation; this includes cardiac fibroblasts. Further, the complexity of TGF-β signaling has been offset by the discovery of members of the SKI family of proteins and their inherent anti-fibrotic properties. In this respect, SKI is a protein that may bind a number of TGF-β associated proteins including SMADs, as well as signaling proteins from other pathways, including Hippo. As SKI is also known to directly deactivate cardiac myofibroblasts to fibroblasts, this mode of action is a putative candidate for further study into the amelioration of cardiac fibrosis. Herein we provide a synthesis of this topic and highlight novel candidate pathways to explore in the treatment of cardiac fibrosis.