The remodeling of Ca2+ homeostasis has been suggested as an important event in driving the expression of the malignant phenotypes, such as proliferation, migration, invasion, and metastasis. Store-operated Ca2+ entry (SOCE) is a predominant Ca2+ entry pathway in epithelial cells. Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum (ER) Ca2+ sensor that triggers SOCE. The functional significance of STIM1-dependent Ca2+ signalings in cancer development and progression has been emerged from studies on breast and cervical cancers. STIM1 overexpression in tumor tissue was noted in 71% cases of early-stage cervical cancer. Tumor expression level of STIM1 was significantly associated with the risk of metastasis and survival, suggesting a diagnostic and prognostic value of STIM1. STIM1-dependent Ca2+ signalings are important for cervical cancer growth, migration, and angiogenesis. Interference with STIM1 expression or blockade of SOCE activity inhibited tumor growth and angiogenesis in animal models, confirming the crucial role of STIM1-mediated Ca2+ influx in aggravating tumor development in vivo. Mechanistic investigations revealed that STIM1 regulates the production of vascular endothelial growth factor (VEGF), a critical stimulator for tumor angiogenesis, from cervical cancer cells. Because of an increase of p21 protein levels and a decrease of Cdc25C protein levels, STIM1-silencing in cervical cancer cells significantly inhibited cell proliferation by arresting the cell cycle at the S and G2/M phases. SOCE activities as well as STIM1 expression were required for epidermal growth factor (EGF)-stimulated cancer cell migration. EGF could stimulate the aggregation and translocation of STIM1 towards to the Orai1-containing regions to mediate SOCE. STIM1-dependent SOCE was necessary for the activation of Ca2+ -regulated protease calpain and Ca2+ -regulated cytoplasmic kinase Pyk2, which regulated the focal-adhesion dynamics of migratory cervical cancer cells. STIM1 silencing also inhibited the recruitment and association of active focal adhesion kinase (FAK) and talin at focal adhesions, indicating the blockade of force transduction from integrin signaling. EGF-induced phosphorylation of myosin II regulatory light chains and actomyosin formation were dependent on STIM1-mediated Ca2+ entry. The direct measurement of cell traction forces revealed that STIM1-dependent Ca2+ signaling regulated the traction force generation at cell adhesions. Taken together, these results highlight the potential role of STIM1-dependent signaling as a target to interfere with cancer malignant behaviors.