A number of metal-organic frameworks (MOFs) employ Zr6O8 clusters as secondary building units (e.g., the UiO-6n series, NU-901, and NU-1000). Open faces on these nodes, whether accidental (i.e., owing to defects) or a fundamental characteristic of the MOF structure, provide well defined sites for the anchoring of other metal-oxide species engineered to have tailored catalytic properties [1]. Theoretical methods [2] can play a key role assisting in the characterization of such species when prepared experimentally, in rationalizing their observed reactivity [3,4], and, importantly, in proposing prior to synthesis targets predicted to exhibit particularly favorable reactivity for specific transformations [5]. This talk will focus primarily on the role theory has played in studying the character of transition-metal catalysts deposited on Zr6O8 nodes and the degree to which reactivities, especially those associated with C-H bond activation reactions, can be tuned with appropriate synthetic design. (Image credit: M. Ortuño and V. Bernales)