Action potential driven neuronal signalling drives several electrical and biochemical processes in the nervous system. However, neurons can maintain synaptic communication and signalling under resting conditions independently of activity. Importantly, these processes are regulated by Ca2+ signals that occur at rest. Several studies have suggested that opening of voltage‐gated Ca2+ channels near resting membrane potentials, activation of NMDA receptors in the absence of depolarization or Ca2+ release from intracellular stores can drive neurotransmitter release as well as subsequent signalling in the absence of action potentials. Interestingly, recent studies have demonstrated that manipulation of resting neuronal Ca2+ signalling yielded pronounced homeostatic synaptic plasticity, suggesting a critical role for this resting form of signalling in regulation of synaptic efficacy and neuronal homeostasis. Given their robust impact on synaptic efficacy and neuronal signalling, neuronal resting Ca2+ signals warrant further mechanistic analysis that includes the potential role of store‐operated Ca2+ entry in these processes. Activity independent synaptic Ca2+ signalling. In central synapses, there is evidence that Ca2+‐induced Ca2+ release (CICR) from endoplasmic reticulum (ER) resident channels such as ryanodine receptors (RyR) can elicit spontaneous neurotransmitter release in the absence of presynaptic action potentials. This form of signalling can be activated by influx of Ca2+ from presynaptic ion channels such as nicotinic acetylcholine receptors or activation of metabotropic receptor pathways (G‐protein coupled receptors or non‐canonical pathways such as Reelin‐mediated activation of APOER2 (also known as LRP8) and VLDLR receptors). The role of the store‐operated Ca2+ entry pathway (SOCE) is beginning to emerge whereby Ca2+ influx through Ca2+ release‐activated Ca2+ channels (ICRAC) can also impact on neurotransmitter release. Classical voltage‐gated Ca2+ channels such as N‐ and P/Q‐type Ca2+ channels have also been shown to play a key role in spontaneous release due to their low probability of opening at resting membrane potentials. The same Ca2+ signalling pathways also play key roles in postsynaptic dendrites, impacting on homeostatic maintenance of synaptic efficacy and regulation of gene transcription, as well as protein translation. The SOCE pathway and CICR (in this case activated by NMDA receptors) are critical for maintenance of dendritic spines via activation of Ca2+‐calmodulin‐dependent kinases such CaMKII and eEF2 kinase. Moreover, L‐ and T‐type voltage‐gated Ca2+ channels have a high propensity to open near resting membrane potentials and regulate synaptic plasticity as well as gene expression.