The effect of environmental stress on the magnitude of inbreeding depression has a long history of intensive study. Inbreeding–stress interactions are of great importance to the viability of populations of conservation concern and have numerous evolutionary ramifications. However, such interactions are controversial. Several meta-analyses over the last decade, combined with omic studies, have provided considerable insight into the generality of inbreeding–stress interactions, its physiological basis, and have provided the foundation for future studies. In this review, we examine the genetic and physiological mechanisms proposed to explain why inbreeding–stress interactions occur. We specifically examine whether the increase in inbreeding depression with increasing stress could be due to a concomitant increase in phenotypic variation, using a larger data set than any previous study. Phenotypic variation does usually increase with stress, and this increase can explain some of the inbreeding–stress interaction, but it cannot explain all of it. Overall, research suggests that inbreeding–stress interactions can occur via multiple independent channels, though the relative contribution of each of the mechanisms is unknown. To better understand the causes and consequences of inbreeding–stress interactions in natural populations, future research should focus on elucidating the genetic architecture of such interactions and quantifying naturally occurring levels of stress in the wild.