Abstract: Neurons are notoriously vulnerable cell types. Even the slightest change in their internal and/or external environments will cause much distress and dysfunction, leading often to their death. A range of pathological conditions, including stroke, head trauma, and neurodegenerative disease, can generate stress in neurons, affecting their survival and proper function. In most neural pathologies, mitochondria become dysfunctional and this plays a pivotal role in the process of cell death. The challenge over the last few decades has been to develop effective interventions that improve neuronal homeostasis under pathological conditions. Such interventions, often referred to as disease-modifying or neuroprotective, have, however, proved frustratingly elusive, at both preclinical and, in particular, clinical levels. In this perspective, we highlight two factors that we feel are key to the development of effective neuroprotective treatments. These are: firstly, the choice of dose of intervention and method of application, and secondly, the selection of subjects, whether they be patients or the animal model. We use the method of red to near-infrared light (λ = 600–1300 nm) treatment as our prime example of why these factors are so important. We then suggest that mitochondria within the distressed neurons form central players in the process and that these organelles, already known to be able to induce cell death, can be the targets for successful neuroprotective intervention.