An increasing number of reports on plant uptake of pharmaceutical compounds (PCs) have been recently published, raising concerns of human exposure through dietary intake. In this study, PC uptake and translocation were evaluated in cucumber and tomato plants to elucidate the effects of PC physicochemical properties, soil type, and irrigation-water quality. Nonionic PCs were taken up and accumulated at higher levels in plants grown in soils of lower organic matter and clay content. While the concentration of most PCs in cucumber and tomato leaves were of similar order, their concentrations in the tomato fruit were much lower than in the cucumber fruit. This is related to differences in fruit physiology. Our data suggest that irrigation with treated wastewater reduces the bioavailability of acidic PCs for uptake by cucumber plants as compared to fresh water irrigation. This study sheds light on factors affecting the uptake of PCs by crops irrigated with treated wastewater, the governing role of PCs' physicochemical properties along with the physiological nature of the plant, soil properties and water quality that together determine uptake, translocation, and accumulation within plant organs. Occurrence of metabolites in plant suggests that PC metabolism has to be evaluated to reveal the total uptake.