Complementary and alternative medicine (CAM) often consists of whole systems of care (such as naturopathic medicine or traditional Chinese medicine (TCM)) that combine a wide range of modalities to provide individualised treatment. The complexity of these interventions and their potential synergistic effect requires innovative evaluative approaches. Model validity, which encompasses the need for research to adequately address the unique healing theory and therapeutic context of the intervention, is central to whole systems research (WSR). Classical randomised controlled trials (RCTs) are limited in their ability to address this need. Therefore, we propose a mixed methods approach that includes a range of relevant and holistic outcome measures. As the individual components of most whole systems are inseparable, complementary and synergistic, WSR must not focus only on the “active” ingredients of a system. An emerging WSR framework must be non-hierarchical, cyclical, flexible and adaptive, as knowledge creation is continuous, evolutionary and necessitates a continuous interplay between research methods and “phases” of knowledge. Finally, WSR must hold qualitative and quantitative research methods in equal esteem to realize their unique research contribution. Whole systems are complex and therefore no one method can adequately capture the meaning, process and outcomes of these interventions.