This study presents a first attempt to assess the mechanisms and potential controls behind past residential mobility through the integration of isotopic data from human inhumations and spatial infrastructural information pertaining to the settlement containing these inhumations. Strontium ( 87 Sr/ 86 Sr) and oxygen (δ 18 O PDB ) isotope data are derived from 200 (post)medieval individuals from the town of Oldenzaal in the present-day Netherlands. Reconstructions of historical route networks show that Oldenzaal was well-connected interregionally throughout the Middle Ages and early-modern times (ca. AD 800–1600). Although the working hypothesis was that in the past a high degree of spatial connectivity of settlements must have been positively related to a highly variable geographical origin of its inhabitants, the isotopic data from Oldenzaal indicate a population characterized by a low variability in terms of their origin. This unexpected result may be caused by (a combination of) various factors, related to (1) biases in the isotopic dataset, (2) interpretative limitations regarding the results of isotopic analyses and (3) the impact of broader socio-cultural factors that cannot be traced through isotopic analyses, such as infrastructural connectivity, socio-economics and political factors. The human oxygen isotope dataset presented here provides a first step towards a δ 18 O PDB reference dataset, against which future samples can be compared without the need to convert the data. This paper establishes that although in archaeology a biomolecular approach potentially provides a detailed reconstruction of the development of past populations in terms of palaeodemography and geographical/cultural origin, such studies should be performed in a transdisciplinary context in order to increase the understanding of the wider controlling factors of past population change.