The observable characteristics and subsequent evolution of young stellar populations is dominated by their massive stars. As our understanding of those massive stars and the factors affecting their evolution improves, so our interpretation of distant, unresolved stellar systems can also advance. As observations increasingly probe the distant Universe, and the rare low-metallicity starbursts nearby, so the opportunity arises for these two fields to complement one another and leads to an improved conception of both stars and galaxies. Here, we review the current state of the art in modeling of massive star-dominated stellar populations and discuss their applications and implications for interpreting the distant Universe. Our principal findings include the following: Binary evolutionary pathways must be included to understand the stellar populations in early galaxies. Observations constraining the extreme ultraviolet spectrum of early galaxies are showing that current models are incomplete. The best current guess is that some form of accretion onto compact remnants is required. The evolution and fates of very massive stars, on the order of 100 M and above, may be key to fully understand aspects of early galaxies.