The purpose of this dissertation is to develop principles and strategies for and identify limitations of multisite cluster randomized trials in the context of partially and fully nested designs. In the first study, I develop principles of estimation, sampling variability, and inference for studies that leverage multisite designs within the context of partially nested structures. In the second study, I further advance multisite partially nested designs by developing expressions to predict the statistical power with which these types of designs can detect main effects and their heterogeneity across sites, as well as expressions to identify optimal sampling plans. In the third study, I examine the impact (and sensitivity) of misspecifying the site-by-treatment variance parameter value on the power and efficiency of multisite cluster-randomized designs with fully nested data. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://bibliotheek.ehb.be:2222/en-US/products/dissertations/individuals.shtml.]