Indoor relative humidity (RH) is commonly used to characterize the indoor environment for heat-air-moisture (HAM) simulations, chamber studies, analysis of monitoring data, or test hut studies of buildings without recognition that indoor RH and condensation potential depend on concurrent outdoor temperature and RH. This can lead to the use of unrealistic boundary conditions for HAM simulations and test programs, which may result in misleading conclusions. In buildings operating without mechanical dehumidification, the indoor air moisture level (vapor pressure) is directly related to the outdoor vapor pressure, moisture sources in the space, and the level of ventilation. Mathematics suggests that one can expect buildings with similar operation, occupancy, and construction, but affected by different weather conditions, to have a similar difference between indoor and outdoor vapor pressures. This paper provides a foundation for selecting appropriate and realistic boundary conditions for the design of residential buildings that are based on vapor pressure difference with the aim to eliminate any significant bias for a particular climate. The paper will present the following: (1) Discussion of current standards that provide some guidance to selecting appropriate indoor moisture levels based on vapor pressure difference; (2) Moisture balance equations will be used to show the impact of ventilation and moisture generation rates on the vapor pressure difference; (3) Monitoring data for six multi-unit residential buildings in two Canadian climates (Toronto and Vancouver) showing the relationship between the outdoor temperatures and vapor pressure difference; (4) Analysis of seasonal indoor moisture conditions and their impact on HAM modeling based on assumed indoor RH and conditions derived by a constant vapor pressure difference; and (5) Exploration of the concept that vapor pressure difference and indoor RH are limited by moisture removal on windows.