This paper addresses the methodological challenges that accompany the use of a combination of research methods to evaluate complex interventions. In evaluating complex interventions, the question about effectiveness is not the only question that needs to be answered. Of equal interest are questions about acceptability, feasibility, and implementation of the intervention and the evaluation study itself. Using qualitative research in conjunction with trials enables us to address this diversity of questions. The combination of methods results in a mixed methods intervention evaluation (MMIE). In this article we demonstrate the relevance of mixed methods evaluation studies and provide case studies from health care. Methodological challenges that need our attention are, among others, choosing appropriate designs for MMIEs, determining realistic expectations of both components, and assigning adequate resources to both components. Solving these methodological issues will improve our research designs and provide further insights into complex interventions.