Descartes' "substance" dualism – postulating both the Self's distinct ontological status and its interaction with the physical world – helped trigger philosophical countermovements that proposed parallelist or reductionist views instead. Today, the mainstream scientific position is that the Self is a fictitious – albeit useful – construct, possibly emerging out of feedback/feedforward loops linking several brain structures. While the details have yet to be worked out and some "hard" problems linger (i.e. the conceptual gap between neural functioning and subjective experience), it is assumed that these will be resolved as neuroscience advances.This presentation argues that our vision of the Self is still evolving in its fundamentals, and not just in the neurological details. For one thing, several physicists and neuroscientists question the brain's status as a strictly "classical" object. If quantum-mechanical microstructures and processes turn out to be relevant to brain functioning, our models of consciousness and the Self may evolve considerably. Second, individuals who have had mystical experiences or who have intense training in mental disciplines systematically report a deep intuition that, behind the phenomenal self, lies a larger reality, a "pure consciousness" that is fundamentally "nonlocal" in nature. Perhaps the most serious challenge comes from parapsychology, a field that has produced substantial evidence for deep – and currently unexplained – connectedness. Properly integrated into a broad, transdisciplinary framework, parapsychology can help define approaches that empirically assess whether the Self is "just" the wetware of our brains, or more like Mind-at-Large.