Sympathetic and parasympathetic regulation of the sinoatrial node (SAN) and atrial myocardium (AM) are associated with leading pacemaker site shits, rate variability, and changes to the effective refractory period (ERP) and Ca2+ transient magnitude, which are potentially linked to the genesis of atrial arrhythmias. In this study we present a realistic and biophysically detailed computer model for simulating the effect of isoprenaline (ISO) and acetylcholine (ACh) on the action potential (AP) and Ca2+ transient of newly developed human SAN and AM myocyte models. These are then incorporated into a 3D model of the human atria with realistic atrial anatomy and SAN complex geometry (Aslanidi et al. 2011). The ISO model incorporates an independent phosphorylation approach (Heijman et al. 2011), which considers individual dose dependencies for each affected substrate. The model accurately reproduced experimental findings at saturating solutions of ISO that the AP in the AM demonstrates a significantly elevated plateau and Ca2+ transient, whereas the APD90 is not significantly changed. This is primarily due to a balance between increased ICaL and IKur channels. At non-saturating solutions, there is no longer a balance between the up-regulation of these channels, and the APD is prolonged. It is also shown that the elevated Ca2+ transient increases the likelihood of Ca2+ and AP alternans. The spontaneous rate of the SAN cell model was increased by ISO. The model of ACh involved a new time dependent formulation of IKACh and a negative shift in If. In the SAN, a reduction in ICaL was also modelled as done in a previous study (Zhang et al. 2002). In the AM, ACh resulted in a significant shortening of the APD and reduced Ca2+ amplitude. In the SAN, a slowing of the pacing rate was observed. In 3D models, ISO resulted in leading pacemaker site shifts within the SAN and an increased pacing rate. It also increased the vulnerability to reentry when the model was paced at high rates. ACh also resulted in leading pacemaker site shifts and was associated with a slowing of the pacing rate and an increased propensity to SAN exit block at high concentrations: the decreased amplitude of the SAN AP combined with the greater repolarising current due to IKACh in the AM resulted in a reduced ability of the SAN to drive the AM. ISO and ACh combined lead to different complex behaviour, such as a reduced pacing rate but increased ability to drive the surrounding AM. In conclusion, we have presented new and novel models of ISO and ACh in the 3D intact model of the human SAN and AM, providing a useful tool for underpinning the functional effects of sympathetic and parasympathetic regulation on atrial arrhythmia genesis.