Lipinski’s Rule of 5 (Ro5) published in 1997 defined the chemical space for oral drug delivery by a molecular weight (MW) ≤ 500 Da, calculated LogP (cLogP) ≤ 5 and ≥ 0, hydrogen bond acceptors (HBAs) ≤ 10, and hydrogen bond donors (HBD) ≤ 5. The Ro5 considered that if more than one of the rules is exceeded it cannot be delivered orally based on the 90th percentile prediction. Twenty-five years after, we analyzed the physicochemical characteristics of the drug products launched over the recent years with regard to the trends in the chemical space from a holistic perspective. The analysis revealed that the Ro5 maintained their validity, but many incremental scientific and technological advances including drug delivery have contributed to broaden the chemical space for oral drug delivery. A review and outlook on the science and technological trends and the emerging opportunities will be discussed.