Homeostatic control of the endoplasmic reticulum (ER) both as the site for protein handling (synthesis, folding, trafficking, disaggregation and degradation) and as a Ca 2+ store is of crucial importance for correct functioning of the cell. Disturbance of the homeostatic control mechanisms leads to a vast array of severe pathologies. The Ca 2+ content of the ER is a dynamic equilibrium between active uptake via Ca 2+ pumps and Ca 2+ release by a number of highly regulated Ca 2+ -release channels. Regulation of the Ca 2+ -release channels is very complex and several mechanisms are still poorly understood or controversial. There is increasing evidence that a number of unrelated proteins, either by themselves or in association with other Ca 2+ channels, can provide additional Ca 2+ -leak pathways. The ER is a dynamic organelle and changes in its size and components have been described, either as a result of (de)differentiation processes affecting the secretory capacity of cells, or as a result of adaptation mechanisms to diverse stress conditions such as the unfolded protein response and autophagy. In this review we want to give an overview of the current knowledge of the (short-term) regulatory mechanisms that affect Ca 2+ -release and Ca 2+ -leak pathways and of the (long-term) adaptations in ER size and capacity. Understanding of the consequences of these mechanisms for cellular Ca 2+ signaling could provide a huge therapeutic potential.