Many studies have quantified pharmaceuticals in the environment, few however, have incorporated detailed temporal and spatial variability due to associated costs in terms of time and materials. Here, we target 33 physico-chemically diverse pharmaceuticals in a spatiotemporal exposure study into the occurrence of pharmaceuticals in the wastewater system and the Rivers Ouse and Foss (two diverse river systems) in the city of York, UK. Removal rates in two of the WWTPs sampled (a conventional activated sludge (CAS) and trickling filter plant) ranged from not eliminated (carbamazepine) to >99% (paracetamol). Data comparisons indicate that pharmaceutical exposures in river systems are highly variable regionally, in part due to variability in prescribing practices, hydrology, wastewater management, and urbanisation and that select annual median pharmaceutical concentrations observed in this study were higher than those previously observed in the European Union and Asia thus far. Significant spatial variability was found between all sites in both river systems, while seasonal variability was significant for 86% and 50% of compounds in the River Foss and Ouse, respectively. Seasonal variations in flow, in-stream attenuation, usage and septic effluent releases are suspected drivers behind some of the observed temporal exposure variability. When the data were used to evaluate a simple environmental exposure model for pharmaceuticals, mean ratios of predicted environmental concentrations (PECs), obtained using the model, to measured environmental concentrations (MECs) were 0.51 and 0.04 for the River Foss and River Ouse, respectively. Such PEC/MEC ratios indicate that the model underestimates actual concentrations in both river systems, but to a much greater extent in the larger River Ouse.