Despite the crucial role of the placenta in supporting pregnancy and fetal development, research into its susceptibility to environmental exposures has been limited by methodological challenges. We review diverse approaches to studying placental biology and responses to chemical exposures, and provide a comprehensive assessment of traditional and emerging methodologies. Beginning with an overview of placental biology and species differences, we evaluate in vivo and in vitro models, and discuss their strengths and limitations. We examine advances, including placental transfer models, toxicokinetic frameworks, and 3D microphysiological systems, for their potential to address current gaps. Last, we consider molecular epidemiology and high-throughput analyses as complementary strategies. Together, these tools support better experimental design and enhance our understanding of placental vulnerability to chemical exposures.