Mitochondria are central to energy metabolism as the source of much of the cell's ATP, as well as being a hub for cellular Ca²⁺ signaling. Mitochondrial Ca²⁺ is a positive effector of ATP synthesis, yet Ca²⁺ overload can lead to mitochondrial dysfunction and cell death. Moreover, Ca²⁺ uptake by mitochondria is involved in shaping cellular Ca²⁺ dynamics by regulating the concentrations of Ca²⁺ within microdomains between mitochondria and sarco/endoplasmic reticulum and plasma membrane Ca²⁺ transporters. Reactive oxygen species (ROS) generated as a consequence of ATP production in the mitochondria are important for cellular signaling, yet contribute to oxidative stress and cellular damage. ROS regulate the activity of redox sensitive enzymes and ion channels within the cell, including Ca²⁺ channels. For both Ca²⁺ and ROS, a delicate balance exists between the beneficial and detrimental effects on mitochondria. In this review we bring together current data on mitochondrial Ca²⁺ uptake, ROS generation, and redox modulation of Ca²⁺ transport proteins. We present a model for crosstalk between Ca²⁺ and ROS signaling pathways within mitochondrial microdomains.