Glutamate, the main excitatory neurotransmitter in the central nervous system, plays an essential role in several cognitive activities such as memorizing and learning. Excessive glutamate release and disturbance of glutamate homeostasis participates in multiple neuronal pathologies including cerebral ischemia (inadequate blood supply), traumatic brain injury (e.g., from a fall or an accident), multiple sclerosis, epilepsy, migraine, fetal hypoxia, or Alzheimer's disease. Attenuating excitotoxicity by, for example, targeting glutamate receptors has proved to be beneficial in animal models but has largely failed in clinical trials because of toxic side effects. New therapeutic concepts have been explored to reduce the excitotoxic effect caused by the excessive glutamate release by using or stimulating glutamate-depleting enzymes in the bloodstream. These enzymes indirectly act upon the brain by depleting glutamate in the bloodstream, which is believed to siphon it out of the brain. Recent studies have shown that bioconjugate approaches applied to such enzymes exacerbate this therapeutic effect but raise additional questions for future research. This Perspective provides an overview of lessons learned by our group when exploring bioconjugate approaches for combatting glutamate excitotoxicity as an illustration of how research on therapeutic bioconjugates is evolving.