This opinion review explores the microbiology of tellurite, TeO32− and selenite, SeO32− oxyanions, two similar Group 16 chalcogen elements, but with slightly different physicochemical properties that lead to intriguing biological differences. Selenium, Se, is a required trace element compared to tellurium, Te, which is not. Here, the challenges around understanding the uptake transport mechanisms of these anions, as reflected in the model organisms used by different groups, are described. This leads to a discussion around how these oxyanions are subsequently reduced to nanomaterials, which mechanistically, has controversies between ideas around the molecule chemistry, chemical reactions involving reduced glutathione and reactive oxygen species (ROS) production along with the bioenergetics at the membrane versus the cytoplasm. Of particular interest is the linkage of glutathione and thioredoxin chemistry from the cytoplasm through the membrane electron transport chain (ETC) system/quinones to the periplasm. Throughout the opinion review we identify open and unanswered questions about the microbial physiology under selenite and tellurite exposure. Thus, demonstrating how far we have come, yet the exciting research directions that are still possible. The review is written in a conversational manner from three long-term researchers in the field, through which to play homage to the late Professor Claudio Vásquez.