Calcium ([Formula: see text]) waves provide a complement to neuronal electrical signaling, forming a key part of a neuron’s second messenger system. We developed a reaction-diffusion model of an apical dendrite with diffusible inositol triphosphate ([Formula: see text]), diffusible [Formula: see text], [Formula: see text] receptors ([Formula: see text]s), endoplasmic reticulum (ER) [Formula: see text] leak, and ER pump (SERCA) on ER. [Formula: see text] is released from ER stores via [Formula: see text]s upon binding of [Formula: see text] and [Formula: see text]. This results in [Formula: see text]-induced-[Formula: see text]-release (CICR) and increases [Formula: see text] spread. At least two modes of [Formula: see text] wave spread have been suggested: a continuous mode based on presumed relative homogeneity of ER within the cell and a pseudo-saltatory model where [Formula: see text] regeneration occurs at discrete points with diffusion between them. We compared the effects of three patterns of hypothesized [Formula: see text] distribution: (1) continuous homogeneous ER, (2) hotspots with increased [Formula: see text] density ([Formula: see text] hotspots), and (3) areas of increased ER density (ER stacks). All three modes produced [Formula: see text] waves with velocities similar to those measured in vitro (approximately 50–90 [Formula: see text]m /sec). Continuous ER showed high sensitivity to [Formula: see text] density increases, with time to onset reduced and speed increased. Increases in SERCA density resulted in opposite effects. The measures were sensitive to changes in density and spacing of [Formula: see text] hotspots and stacks. Increasing the apparent diffusion coefficient of [Formula: see text] substantially increased wave speed. An extended electrochemical model, including voltage-gated calcium channels and AMPA synapses, demonstrated that membrane priming via AMPA stimulation enhances subsequent [Formula: see text] wave amplitude and duration. Our modeling suggests that pharmacological targeting of [Formula: see text]s and SERCA could allow modulation of [Formula: see text] wave propagation in diseases where [Formula: see text] dysregulation has been implicated.