Research on the therapeutic potential of psychedelics has surged, prompting a re-examination of the role of set and setting in psychedelic-assisted therapy. Yet, these concepts are vague and typically defined over inclusively. We believe that set and setting research should be methodologically reductionist, focusing on specific components rather than set and setting as such. To that end, we propose the mechanism-first approach, which begins with specific, paradigmatic set and setting components, such as "openness to the psychedelic experience" or calming lighting and music. It seeks to understand the mechanisms through which these components affect psychedelic outcomes. Once the mechanisms in paradigmatic cases are understood, researchers can ask whether other mental and environmental factors play the same or similar mechanistic roles. As the process iterates over time, understanding of set and setting expands to include more components. Setting aside the vague, standard definitions of set and setting and focusing, instead, on specific components of set and setting, the mechanism-first approach encourages productive research agendas, focused on specific projects that are mutually informative. To defend it, we outline the problems with standard definitions of set and setting, describe the mechanism-first approach in detail, illustrate it by considering its implications for selected, active research projects, and respond to objections to our approach.