Pessoa's precis The Entangled Brain is a call to action. The larger concepts resonate with existing complex systems frameworks in general and in neuroscience in particular, especially in the fields of connectomics and criticality [Cocchi, L., Gollo, L. L., Zalesky, A., & Breakspear, M. Criticality in the brain: A synthesis of neurobiology, models and cognition. Progress in Neurobiology, 158, 132–152, 2017; Bassett, D. S., & Gazzaniga, M. S. Understanding complexity in the human brain. Trends in Cognitive Sciences, 15, 200–209, 2011]. What is provocative from our perspective is that despite recognizing the brain as a complex system, the experimental approaches adopted by our community largely fail to align with this recognition. In this commentary, we lay out the fundamental challenge Pessoa brings to the neuroscience community: to engage with the brain, conceptually and experimentally, as a complex whole.