Compound lipophilicity is a fundamental physicochemical property that plays a pivotal role in the absorption, distribution, metabolism, and elimination (ADME) of therapeutic drugs. Lipophilicity is expressed in several different ways, including terms such as Log P, clogP, delta Log P, and Log D. Often a parabolic relationship exists between measured lipophilicity and in vivo brain penetration of drugs, where those moderate in lipophilicity often exhibit highest uptake. Reduced brain extraction of more lipophilic compounds is associated with increased non-specific binding to plasma proteins. More lipophilic compounds can also be more vulnerable to P450 metabolism, leading to faster clearance. Very polar compounds normally exhibit high water solubility, fast clearance through the kidneys, and often contain ionizable functional groups that limit blood-brain barrier (BBB) penetration. The brain penetration and specific to non-specific binding ratios exhibited in vivo by positron emission tomography (PET) and single photon emission computed tomography (SPECT) radiotracers involves a complex interplay between many critical factors, including lipophilicity, receptor affinity, metabolism, molecular size and shape, ionization potential, and specific binding to BBB efflux pumps or binding sites on albumin or other plasma proteins. This paper explores situations in which lipophilicity is a good predictor of BBB penetration, as well as those where this correlation is poor. The more commonly used methods for measuring lipophilicity are presented, and the various terms often found in the literature outlined. An attempt is made to describe how this information can be used in optimizing the development of PET and SPECT tracers that target the central nervous system (CNS).