Abstract: The challenge of protecting the brain resides in the unique characteristics of neurons, as they are postmitotic, long-lived, excitable, and polarized cells with long and fragile axons and dendrites. The complexity of the multiple potential cell death pathways further complicates this issue. In addition, the immature brain is prone to a “cell death continuum,” which involves intricate molecular interconnections between cell death processes. This makes finding safe and effective neuroprotective strategies to prevent damage to the developing brain a significant challenge in neonatology. The only approved treatment for term newborns with hypoxic-ischemic encephalopathy (HIE) is therapeutic hypothermia. However, access to this treatment and its effectiveness is limited to a few cases. Research is focused on developing new neuroprotective agents that can be combined with hypothermia to improve its therapeutic window and outcome.