Adverse effects associated with chemical exposures during pregnancy include several developmental and reproductive disorders. However, considering the tens of thousands of chemicals present on the market, the effects of chemical mixtures on the developing fetus is still likely underestimated. In this critical review, we discuss the potential to apply innovative biomonitoring methods using high-resolution mass spectrometry (HRMS) on placenta to improve the monitoring of chemical exposure during pregnancy. The physiology of the placenta and its relevance as a matrix for monitoring chemical exposures and their effects on fetal health is first outlined. We then identify several key parameters that require further investigations before placenta can be used for large-scale monitoring in a robust manner. Most critical is the need for standardization of placental sampling. Placenta is a highly heterogeneous organ, and knowledge of the intraplacenta variability of chemical composition is required to ensure unbiased and robust interindividual comparisons. Other important variables include the time of collection, the sex of the fetus, and mode of delivery. Finally, we discuss the first applications of HRMS methods on the placenta to decipher the chemical exposome and describe how the use of placenta can complement biofluids collected on the mother or the fetus.