Several methods for testing mediation hypotheses with 2-level nested data have been proposed by researchers using a multilevel modeling (MLM) paradigm. However, these MLM approaches do not accommodate mediation pathways with Level-2 outcomes and may produce conflated estimates of between- and within-level components of indirect effects. Moreover, these methods have each appeared in isolation, so a unified framework that integrates the existing methods, as well as new multilevel mediation models, is lacking. Here we show that a multilevel structural equation modeling (MSEM) paradigm can overcome these 2 limitations of mediation analysis with MLM. We present an integrative 2-level MSEM mathematical framework that subsumes new and existing multilevel mediation approaches as special cases. We use several applied examples and accompanying software code to illustrate the flexibility of this framework and to show that different substantive conclusions can be drawn using MSEM versus MLM.