Deactivation mechanisms for a rhenium-promoted titania-supported cobalt catalyst are investigated during Fischer-Tropsch (FT) synthesis. Bench-scale reactor tests, chemisorption studies, thermogravimetric analyses (TG), and transmission electron microscopy (TEM) are used to probe environmental effects on catalytic activity. Bench-scale reactor studies show a steady decrease in activity with time. While a fraction of this loss can be recovered with a low temperature reduction (rejuvenation) inside the reactor, multiple data indicate this phenomenon is primarily attributable to water-induced oxidation of small cobalt particles. Data from long-term FT runs indicate the presence of three non-rejuvenable deactivation mechanisms: metal agglomeration, strong metal-support interaction (SMSI), and mixed metal oxide formation. High conversion studies implicate byproduct water in the agglomeration process, and ex-situ TEM data conclusively reveals that growth occurs via a coalescence mechanism. Combined kinetic and chemisorption studies reveal that SMSI results from the gradual buildup of titania decoration on the surface of the active cobalt and is exacerbated with multiple rejuvenation cycles. TGA data indicate that mixed metal oxide formation occurs in long-duration, pilot plant runs. In all cases, the aggregate of reactor kinetic, chemisorption, TG, and TEM results point to chemically-assisted deactivation phenomena attributable to the byproduct water.