Successful drug delivery across the blood-brain barrier (BBB) represents the most significant hurdle in the identification of central nervous system (CNS) therapeutics. The magnitude of the problem is best exemplified by estimates that 98% of small molecule drugs fail to cross the BBB. Cytochrome P450 (CYP) mediated metabolism further limits brain uptake by reducing drug bioavailability, as well as compromising patient safety and drug efficacy. The underlying influence of small molecule properties on these biological phenomena represents a critical feature affecting both pharmacokinetics and pharmacodynamics across discovery platforms. Thus, the overall hypothesis addressed by this research is that analyses of small molecule properties can serve as project management tools in CNS-focused drug discovery campaigns. First, we created and analyzed molecular properties trends in a new small molecule CYP2D6 substrate database. CYP2D6 disproportionately metabolizes CNS drugs at a higher rate compared to other marketed drugs making it an important consideration in CNS drug discovery. Second, the informatics studies were complemented by experimental investigation of the molecular properties and molecular basis for differential CYP2D6 substrate status between two related CNS therapeutics. Finally, through structured literature mining we assembled a small molecule database of CNS-penetrant compounds and analyzed molecular properties trends. These results provide a unique retrospective analysis of the successes and failures in prior CNS therapeutic development, as well as providing feasibility data for the future development of forecasting tools to address CYP involvement and CNS penetration.