The remodeling of Ca²⁺ homeostasis has been implicated as a critical event in driving malignant phenotypes, such as tumor cell proliferation, motility, and metastasis. Store-operated Ca²⁺ entry (SOCE) that is elicited by the depletion of the endoplasmic reticulum (ER) Ca²⁺ stores constitutes the major Ca²⁺ influx pathways in most nonexcitable cells. Functional coupling between the plasma membrane Orai channels and ER Ca²⁺-sensing STIM proteins regulates SOCE activation. Previous studies in the human breast, cervical, and other cancer types have shown the functional significance of STIM/Orai-dependent Ca²⁺ signals in cancer development and progression. This article reviews the information on the regulatory mechanisms of STIM- and Orai-dependent SOCE pathways in the malignant characteristics of cancer, such as proliferation, resistance, migration, invasion, and metastasis. The recent investigations focusing on the emerging importance of SOCE in the cells of the tumor microenvironment, such as tumor angiogenesis and antitumor immunity, are also reviewed. The clinical implications as cancer therapeutics are discussed.