Set and setting is a fundamental concept in the field of psychedelic studies, denoting the crucial importance of context to determining the character and quality of experiences with psychedelics. This paper suggests a framework for thinking of set and setting and its relevance for psychedelic harm reduction. It discusses how "set," the diverse factors related to an individual's mindset, and "setting," the diverse environmental dimensions, influence the psychedelic experience and its outcomes, and the relevance to the field of harm reduction. It additionally provides an overview of four basic modalities of set and setting, the therapeutic, the clinical trial, the ritualistic, and the recreational, examining the differences in set and setting between each and the other according to several key parameters, the implications of such differences, and the ways in which harm reduction strategies informed by the principles of set and setting can be integrated to increase safety and benefits in each case. The integration of set and setting principles into public health policies, alongside education on their significance, could further the efficacy of harm reduction programs in the field of psychedelics.