The focus of this chapter is on understanding the complexity associated with the resistance to flow through the pulmonary circulation. Pulmonary vascular resistance (PVR) is a variable that reflects the physical size (diameter and length) of the vascular tree at any moment in time. If PVR is increased, then it will take more energy for the right ventricle to pump the venous return through the lungs. One obvious complexity with the magnitude of the PVR is that the pulmonary resistance changes with lung inflation. There may also be resistance changes in response to various stimuli, as well as in different lung pathologies, and it can play an important role in the impact of heart–lung interactions. Although it is easy to define pulmonary resistance analogous to Ohm’s law, the underlying basis of pathophysiologic changes in this resistance is neither simple nor always intuitive, and it is important to understand the limitations of this measurement. A fundamental issue in the interpretation (or even definition) of PVR involves uncertainty about what downstream pressure to use (and how to measure it in vivo). A ubiquitous understanding of the pulmonary vasculature today revolves around the three zones of the lung as defined by West et al. In an upright human, a certain fraction of the lung would be in a zone 2 condition, where alveolar pressure becomes the effective downstream pressure. However, at any given time, there will always be a mixture of zones in the pulmonary circulation, so how can one define or measure the PVR? In addition to this puzzle, there are changes in PVR related to the effect of lung inflation on different serial regions of the pulmonary vasculature, as well as effects of the nonlinear distensibility of the elastic vessels. In what follows, we deal with these issues in an effort to define when and where it might be appropriate to measure the PVR, and more importantly how it might be useful in physiologic research and clinical settings.