Calcium electroporation is a potential novel anticancer treatment, where high concentrations of calcium are introduced into the cell cytosol by electroporation. This is a method where short, high-voltage pulses induce a transient permeabilization of the cell membrane and thereby allow influx and efflux of ions and molecules. Electroporation is used in combination with chemotherapeutic drugs (electrochemotherapy) as a standard treatment for cutaneous metastases, and electroporation using a higher electric field and number of pulses (irreversible electroporation) is increasingly being used as an anticancer treatment. In this review, calcium electroporation is described with emphasis on the investigations of differences in the effect on normal and malignant cells and tissues in vitro and in vivo. Calcium electroporation has been shown to induce cell death in vitro and tumor necrosis in vivo with a difference in sensitivity between different tumor types. Normal cells treated in vitro are significantly less affected than cancer cells, and a similar trend is shown in vivo where muscle and skin tissue surrounding a treated tumor as well as muscle and skin directly treated with calcium electroporation were less affected than tumors. The mechanism behind this difference in sensitivity is not fully understood but might be affected by differences in electric impedance, membrane repair, and expression of plasma membrane calcium ATPases in normal and malignant cells. The research on calcium electroporation shows a potential novel anticancer treatment with significant effect on cancer cells and tissues while normal cells and tissues are clearly less affected.