Resistance against CNS drugs may arise from various mechanisms, with limited drug penetration across the blood-brain barrier (BBB) being a significant contributing factor. The BBB employs efflux transporters like P-glycoprotein (P-gp) to safeguard the brain by removing toxins and xenobiotics, however, P-gp also pumps out therapeutic drugs, and its upregulation in disease states can contribute to variability in drug response. While inhibiting P-gp to prevent drug efflux seems appealing, it could lead to toxicity since P-gp is also important for expulsion of toxins from the brain. This necessitates the incorporation of P-gp substrate liability assessment into early drug discovery stages using appropriate experimental approaches. Therefore, this review aims to draw interest in this crucial area by analyzing the existing research on P-gp's impact on brain distribution of major CNS drugs and exploring the detection methods for identifying P-gp substrates. By identifying confirmed P-gp substrates and evaluating effective detection methods, this work emphasizes the continued importance of monitoring P-gp-mediated CNS drug efflux out of the brain tissue. This knowledge can empower clinicians to anticipate potential treatment inefficacy and guide therapeutic decision-making, ultimately leading to improved patient treatment outcomes.