Cellular proliferation and division are central processes in the development, survival and evolution of living systems. Transitioning into the cell division phase of the cell cycle encompasses dramatic remodeling of cellular organelles and signaling modules including Ca2+ signaling. As well, Ca2+ signals play important roles during progression through various stages of the cell cycle. A ubiquitous Ca2+ influx pathway that is activated based on intracellular Ca2+ store content is store-operated Ca2+ entry (soce). SOCE is activated through a complex interplay between a Ca2+ channel at the cell membrane, Orai1, and a Ca2+ sensor that localizes to the endoplasmic reticulum, STIM1. Herein, we discuss potential roles and regulation of STIM and Orai proteins during cellular proliferation.