The human relationship with mortality has been widely studied in psychology research, with an extensive record suggesting that death-related stimuli impact behavior, even without conscious awareness. Yet, little is known about the underlying brain activity. In this systematic review, we aimed to examine whether there is something distinctive about the neural processing of death-related stimuli. We conducted a literature search to find studies where participants had been presented with death-related vs. other negatively valenced stimuli while undergoing functional brain imaging scanning. Seven functional magnetic resonance imaging (fMRI) studies with a total of 204 participants adhered to our criteria. Five of six studies that used whole-brain analysis found that unpleasant stimuli consistently elicited increased insular activity, but only when it was unrelated to mortality. This suggests a difference between the neural processing of death and other threats. We discuss possible interpretations and speculate that it is related to the insula’s role in sense of self and assessment of threat. Further research is needed to determine whether this marker is robust and what its function and consequences may be. A better understanding of how individuals process death-related information promises deeper insight into the human relationship with mortality. Bringing to light the nature of this relationship has significant implications for individuals and society, not least for mental health interventions and end-of-life care.