Synaptic transmission relies on rapid calcium (Ca) influx into presynaptic terminal via voltage-gated Ca channels. However, smooth ER is present in presynaptic terminals and accumulating evidence indicate that ER Ca signaling may play a modulatory role in synaptic transmission. Most recent publication by Lindhout and colleagues (EMBO J, 38 (2019) e101345) suggested that the fragmentation state of the ER affects synaptic vesicle release. Here we discuss these results as well as several key publications that addressed a connection between ER Ca signaling and synaptic transmission.