This article focuses on the interactions between individual differences and building characteristics that may occur during multi-level wayfinding. Using the Seattle Central Library as our test case, we defined a series of within-floor and between-floor wayfinding tasks based on different building analyses of this uniquely designed structure. Tracking our 59 participants while they completed assigned tasks on-site, we examined their wayfinding performance across tasks and in relation to a variety of individual differences measures and wayfinding strategies. Both individual differences and spatial configuration, as well as the organization of the physical space, were related to the wayfinding challenges inherent to this library. We also found wayfinding differences based on other, non-spatial features, such as semantic expectations about destinations. Together, these results indicate that researchers and building planners must consider the interactions among building, human, and task characteristics in a more nuanced fashion.