Background <p>Cardiac fibroblasts (CFs) are numerically a highly abundant cell type in the heart and are responsible for the homeostasis of the extracellular matrix (ECM) in the myocardium under normal conditions. Upon cardiac stress, these cells become activated and transdifferentiate into myofibroblasts (MyCFs), which are characterized by their increased capacity to proliferate, migrate, and secrete ECM components and bioactive molecules. The trans-differentiation of CFs is induced by several factors like angiotensin II (Ang II) and transforming growth factor-ß (TGF-ß and is crucial in cardiac remodeling. In recent years, signal mechanisms playing a role in MyCFs behavior have been intensively investigated, including the role of the universal second messenger calcium (Ca²⁺).</p> Aims and scope <p>Here, we review the current knowledge on Ca²⁺ handling and Ca²⁺-dependent signal transduction in cardiac (myo)fibroblasts, with a focus on the mechanisms leading to intracellular Ca²⁺ release and Ca²⁺ entry from the extracellular space, which is involved in the generation of Ca²⁺ transients and regulation of Ca²⁺ oscillation. Moreover, the activation of Ca²⁺-induced signal transduction involving different kinases and the phosphatase calcineurin in CFs is described.</p> Graphical Abstract <p>This review explores Ca²⁺ handling and signaling in cardiac fibroblasts, including intracellular release, extracellular entry, and Ca²⁺-dependent pathways, highlighting their role in myofibroblast behavior and cardiac remodeling processes.</p> <p></p>