The strategic use of fluorine substitution in drug discovery and drug development is well documented. The small size and high electronegativity of fluorine are among properties of this element that lend special advantages. Applications in drugs targeted to the central nervous system (CNS) have been particularly fruitful in addition to favorable properties seen in many peripherally acting drugs. Fluorine substitution can be used to solve problems unique to the CNS, such as blood brain barrier (BBB) penetration. Likewise, use of the positron emitting isotope, (18)F, provides a unique tool for non-invasive imaging and diagnoses in the CNS. In this review, fluorine in CNS drugs and drug discovery are discussed.