We will discuss recent evidence revealing that some members of the Ca2+ transportome (i.e., MCU, MCU regulator 1 (MCRU1), TRPC6, and STIM1) notably impact intracellular Ca2+ level, mitochondrial ROS (mtROS) production, and transcriptomic profiles, and how these deregulations specifically promote HCC progression. The gene discussed is STIM1; the disease is hepatocellular carcinoma.