Mass timber structures have the potential to change wooden construction on a global scale. Numerous mass timber high-rise buildings are in planning, under development or already built and their performance will alter how architects and engineers view wood as a material. To date, the discussion of material durability and biodegradation in these structures has been limited. While all materials can be degraded by wetting, the potential for biodegradation of wood in a mass timber building requires special consideration. Identifying and eliminating the conditions that might lead to this degradation will be critical for ensuring proper performance of wood in these structures. This article reviews and contrasts potential sources of biodegradation that exist for traditional wood construction with those in mass timber construction and identifies methods for limiting the degradation risk. Finally, future research needs are outlined.