This contribution to the Brain Sciences in the Courtroom Symposium identifies and discusses issues important to admissibility determinations when courts confront brain-scan evidence. Through the vehicle of the landmark 2010 federal criminal trial U.S. v. Semrau (which considered, for the first time, the admissibility of brain scans for lie detection purposes) this article highlights critical evidentiary issues involving: 1) experimental design; 2) ecological and external validity; 3) subject compliance with researcher instructions; 4) false positives; and 5) drawing inferences about individuals from group data. The article’s lessons are broadly applicable to the new wave of neurolaw cases now being seen in U.S. courts.