This introduction examines major issues and challenges as presented in this special issue of Prevention Science, “Challenges to the Dissemination and Implementation of Evidence Based Prevention Interventions for Diverse Populations.” We describe the Fidelity-Adaptation Dilemma that became the origin of dynamic tensions in prevention science. It generated controversies and debates and new perspectives on the dissemination and implementation of evidence-based interventions (EBIs) within diverse populations. The five articles in this special issue address many of these challenges. These dynamic tensions have culminated in a reframing of this dilemma, that now argues that fidelity and adaptation are both equally important imperatives. These five articles also examine the abiding challenges of engagement and sustainability. Also, two commentaries from expert research investigators reflect on these five articles and their contributions to prevention science. The current introduction describes this “second generation” of EBI’s as they may contribute towards a reduction of the health disparities and inequities that disproportionately affect sectors of the major ethnocultural populations in the U.S. We also present a systems analysis of approaches and challenges in the dissemination and implementation of EBI’s within the contemporary integrative care environment. Finally, we mention an initiative for, “building a science of intervention adaptation,” that proposes systematic research and the creation of an archive of scientific data on the benefits and problems of intervention adaptation. Collectively these new directions can integrate scientific rigor and sensitivity to cultural factors, for enhancing the effectiveness and reach of this second generation of evidence-based interventions with diverse ethnocultural populations.