Cardiac fibroblasts play an important role in cardiac fibrogenesis which associated with a variety of heart diseases including atrial fibrillation (AF). However, the Ca2+ permeable channels which are responsible for cellular functions of fibroblasts remain unknown. Here, we investigated the potential role of TRPM7‐mediated Ca2+ entry is involved in fibroblast differentiation. With consent, fibroblasts were obtained from patients undergoing cardiac surgery. The isolated fibroblast cells were used for patch‐clamp, Ca2+ image and immunostaining. TRPM7 siRNA was used to knock‐down TRPM7 expression when it was necessary. A typical TRPM7‐like current obtained from isolated fibroblasts by patch‐clamping. TRPM7 siRNA decreased the current density by 76%, confirming it was TRPM7. Interestingly, the current in AF patients were 3 folds bigger than those in control patients suggest that TRPM7 play a role in AF. Immunostaining results showed basal level of differentiation was much higher in cells from AF patients than those from control patients. TRPM7 siRNA significantly decreased TGF‐β1 induced fibroblast differentiation in both control and AF patients. To conclude, our study provided a novel molecule (TRPM7) as well as a novel mechanism for cardiac fibrogenesis: TRPM7‐mediated Ca2+ signal is important in cardiac fibroblast differentiation, which largely contributes to cardiac fibrogenesis cascade and related heart diseases. Project supported by NIH # HL 078960