Healthcare is dealing with a series of challenges such as chronic conditions, aging populations, climate change, staff shortages, stringent legislations, and financial constraints. It is well accepted that these challenges require complex responses, generally called “complex interventions.” However, to be effective, they need a specific research and evaluation approach. In this chapter, we will describe what makes an intervention complex and why we study them in a different way. We will describe various complex intervention frameworks which complements the discussion of evaluation frameworks and theories in chapter “Evaluation of Implementation: A Taxonomy of Implementation Science Theories, Models and Frameworks” in this handbook. We will discuss the development of complex interventions, pilot and feasibility testing for complex interventions, and several evaluation and implementation strategies, mainly applicable in organizational change and practice change evaluations.