In addition to adjusting the expression and activity of the canonical STIM1-Orai1 signaling axis, cancer cells also have developed the ability to switch to store-independent Ca2+ entry to escape a potentially “doomed fate.” It was not until the 1990s that an alternative “store-independent Ca2+ entry” model was proposed to provide a more accurate depiction of Ca2+ entry under a physiological level of agonists. This evidence concerns the gene STIM1 and cancer.