Neurodegeneration is increasingly recognized not only as a disorder of neurons but also as a breakdown of dialogue between the nervous and immune systems. Recent discoveries reveal that immune cells and inflammatory signals are deeply interwoven with brain function across the lifespan. Far from passive responders, immune cells act as sentinels and shapers of neuronal resilience, vulnerability, and repair. Together, robust data support a model in which neurodegeneration emerges from complex interactions between neural and immune networks, positioning the immune system as both a sensor and driver of brain health. This perspective synthesizes a growing body of work arguing that neurodegenerative diseases are a failure of neuroimmune crosstalk—where protective signals are lost, and maladaptive responses take hold. By restoring immune homeostasis, fine-tuning inflammatory responses, or targeting epigenetic regulators of the immune state, it may be possible not only to slow degeneration but also to promote recovery. We outline the key challenges and opportunities for this paradigm shift and highlight how a deeper integration of neuroscience and immunology could transform the future of treating neurodegenerative diseases. Lastly, we describe critical focus areas to improve our understanding of neurodegeneration and highlight the development of immune-based therapeutics for neurodegeneration.