While there is a large body of evidence indicating that sexual minority youth experience inequitably high rates of mental health problems (eg, depression, suicidality), we know little about how temporal changes in sexual attractions, identities and behaviour may impact mental health (and other) outcomes. In this essay, we review existing research regarding sexual fluidity and mental health among young adults in order to identify critical knowledge gaps with respect to an epidemiological understanding of the relationship between these factors. We describe three gaps that in turn inform a larger public health research agenda on this topic. First, there are a number of methodological challenges given that fluidity can occur over short or long periods of time and across multiple dimensions of sexual orientation (eg, attractions, identities and behaviour) with various patterns (eg, directionality of change). Tailored measures that accurately and inclusively reflect diversities of sexual fluidity trajectories are needed. Second, causal relationships between sexual fluidity and mental health remain uncertain and unquantified. Third, little is known about how features of context (eg, gender norms and political climate) influence youth experiences with sexual fluidity and mental health. Finally, we propose a set of recommendations to address these knowledge gaps to improve the quality of epidemiological research involving young people.