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.