Significance Plant growth requires a balanced supply of mineral nutrients. However, the availability of minerals varies constantly in the environment. How do plants adapt to low or high levels of minerals in the soil? The answer to this question holds the key to sustainable crop production. Mg is an essential macronutrient for plants, but high levels of Mg 2+ can become toxic. This study uncovered a regulatory mechanism, consisting of two calcineurin B-like (CBL) Ca sensors partnering with four CBL-interacting protein kinases (CIPKs) forming a CBL–CIPK network that allows plant cells to sequester the extra Mg 2+ into vacuoles, thereby protecting plant cells from high-Mg toxicity. To our knowledge, this report is the first that describes such a signaling mechanism for regulation of Mg homeostasis.