While prior research has extensively evaluated the performance advantage of moving from a 2D to a 3D design style, the impact of process parameter variations on 3D designs has been largely ignored. In this paper, we attempt to bridge this gap by proposing a variability-aware design framework for fully-synchronous (FS) and multiple clock-domain (MCD) 3D systems. First, we develop analytical system-level models of the impact of process variations on the performance of FS 3D designs. The accuracy of the model is demonstrated by comparing against transistorlevel Monte Carlo simulations in SPICE - we observe a maximum error of only 0:7% (average 0:31% error) in the mean of the maximum critical path delay distribution. Second, to mitigate the impact of process variations on 3D designs, we propose a variability-aware 3D integration strategy for MCD 3D systems that maximizes the probability of the design meeting specified system performance constraints. The proposed optimization strategy is shown to significantly outperform FS and MCD 3D implementations that are conventionally assembled - for example, the MCD designs assembled with the proposed integration strategy provide, on average, 44% and 16:33% higher absolute yield than the FS and conventional MCD designs respectively, at the 50% yield point of the conventional MCD designs.