The article reviews the fundamental physiochemical features and pharmacokinetic properties of drugs that successfully cross the blood-brain barrier (BBB) and exhibit central nervous system (CNS) activity. Key factors include molecular weight, lipophilicity, hydrogen bond donor and acceptor capacity, solubility, permeability, metabolic stability, protein binding, and hERG inhibition. The balance between optimizing these properties is critical for designing drugs that can effectively penetrate the BBB and affect relevant biological systems. The introduction highlights the challenges in designing drugs that can cross the BBB, emphasizing the importance of passive diffusion, active transport, and efflux mechanisms. The article also discusses the role of high-throughput screening, combinatorial chemistry, and informatics in drug discovery, and the significance of computational approaches in predicting BBB penetration. The QSAR studies and computational methods used to predict BBB penetration are detailed, including the use of polar surface area (PSA), molecular volume, and hydrogen bonding descriptors. The article concludes with a summary of the key physical-chemical and pharmacokinetic properties of successful CNS drugs, emphasizing the need for a balance between potency, selectivity, and other biological parameters to ensure effective drug-like properties.The article reviews the fundamental physiochemical features and pharmacokinetic properties of drugs that successfully cross the blood-brain barrier (BBB) and exhibit central nervous system (CNS) activity. Key factors include molecular weight, lipophilicity, hydrogen bond donor and acceptor capacity, solubility, permeability, metabolic stability, protein binding, and hERG inhibition. The balance between optimizing these properties is critical for designing drugs that can effectively penetrate the BBB and affect relevant biological systems. The introduction highlights the challenges in designing drugs that can cross the BBB, emphasizing the importance of passive diffusion, active transport, and efflux mechanisms. The article also discusses the role of high-throughput screening, combinatorial chemistry, and informatics in drug discovery, and the significance of computational approaches in predicting BBB penetration. The QSAR studies and computational methods used to predict BBB penetration are detailed, including the use of polar surface area (PSA), molecular volume, and hydrogen bonding descriptors. The article concludes with a summary of the key physical-chemical and pharmacokinetic properties of successful CNS drugs, emphasizing the need for a balance between potency, selectivity, and other biological parameters to ensure effective drug-like properties.