Recent studies have reported the existence of resident cardiac stem cells (CSCs) that are clonogenic, self-renewing and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. However, the signals regulating the proliferation of CSCs have been less extensively studied. Stem cell antigen-1 (Sca-1)+ CSCs were isolated by sorting using the magnetic cell sorting system from heart of ICR mice. The purity of Sca-1+ cells was confirmed by flow cytometry. The effects of cytokines, growth factors and signal pathway inhibitors to the proliferation of Sca-1+ CSCs were assayed by BrdU labeling. Flow cytometry analysis showed that the purity of Sca-1+ CSCs was more than 87%. Among cytokines and growth factors examined in this study, basic fibroblast growth factor (bFGF), FGF4, and epidermal growth factor (EGF) stimulated significantly the proliferation of Sca-1+ CSCs (control, 100짹4.51 vs. bFGF, 202.19짹19.97 vs. FGF4, 160.57짹5.92, vs. EGF, 130.03짹3.66, P < 0.05, respectively). Two chemical signal transducer and activator of transcription 3 (STAT3) pathway inhibitors, piceatannol (JAK1/STAT3 inhibitor) and AG490 (JAK2/STAT3 inhibitor) prevented both bFGF- and FGF4-induced proliferation of Sca-1+ CSCs (bFGF+piceatannol, 59.95% vs. bFGF+AG490, 75.13% vs. FGF4+piceatannol, 64.12% vs. FGF4+AG490, 80.18%, respectively, P< 0.05). Moreover, phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002 also blocked both bFGF- and FGF4-induced proliferation of Sca-1+ CSCs (bFGF+LY294002, 71.91% vs. FGF4+LY294002, 86.16%). However, mitogen-activated protein kinase (MAPK) inhibitor, PD98059 and a specific inhibitor of MEK (MAPK/ERK kinase), U0126 had no effect on the proliferation of Sca-1+ CSCs. These data demonstrated that FGFs promote the proliferation of Sca-1+ CSCs through the activation of JAK/STAT3 and PI3-K signal pathway.