Drugs may be administered via different routes, with the oral route generally preferred for ease and patient compliance. Absorption occurs through membranes, and early studies (Collander & Bärlund, 1932; 1971) identified molecular size, lipophilicity, and hydrogen bonding as key to membrane uptake—understanding of these properties has grown, leading to current concepts on optimal physical properties. A major hurdle between compounds with high target affinity and successful drugs is poor absorption and pharmacokinetics, a main cause of attrition in drug development. It is now widely recognized that physicochemical, pharmacokinetic, and biopharmaceutical properties must be addressed early in drug discovery. Studies using neural networks, decision trees, or Bayesian methods have explored "drug-likeness" (e.g., distinguishing CNS-active/inactive drugs), and analyzing the World Drug Index led to the rule-of-5 (poor absorption likely if molecular weight >500, CLOGP >5, H-bond donors >5, H-bond acceptors >10). We propose "property-based design"—encompassing physicochemical, pharmacokinetic, and toxicokinetic properties—as a tool for medicinal chemists. This Perspective first covers aspects of biological barriers' properties, then examines estimation of drug absorption via key barriers (gastrointestinal tract, blood-brain barrier, skin). It discusses approaches for measuring and computing physicochemical/molecular properties used in absorption optimization, and finally explores using these properties to design optimal pharmacokinetic profiles.