This article serves as a practical guide to mediation design and analysis by evaluating the ability of mediation models to detect a significant mediation effect using limited data. The cross-sectional mediation model, which has been shown to be biased when the mediation is happening over time, is compared with longitudinal mediation models: sequential, dynamic, and cross-lagged panel. These longitudinal mediation models take time into account but bring many problems of their own, such as choosing measurement intervals and number of measurement occasions. Furthermore, researchers with limited resources often cannot collect enough data to fit an appropriate longitudinal mediation model. These issues were addressed using simulations comparing four mediation models each using the same amount of data but with differing numbers of people and time points. The data were generated using multilevel mediation models, with varying data characteristics that may be incorrectly specified in the analysis models. Models were evaluated using power and Type I error rates in detecting a significant indirect path. Multilevel longitudinal mediation analysis performed well in every condition, even in the misspecified conditions. Of the analyses that used limited data, sequential mediation had the best performance; therefore, it offers a viable second choice when resources are limited. Finally, each of these models were demonstrated in an empirical analysis. [For a related report, see ED588330.]