Approximately 6% of orally administered drugs have physicochemical properties that are beyond Lipinski's rule of five (bRo5). However, in the past five years, there have been 22 new oral bRo5 drugs approved by the FDA, which account for 21% of new oral drug approvals. The significant increase in the percentage of bRo5 drug approvals represents a shift in the types of drug targets undertaken by medicinal chemists including a larger number of protein–protein interaction (PPI) inhibitors, such as BCL-2 inhibitors, and nontraditional drug targets such as NS5A inhibitors for the treatment of hepatitis C (HCV). The shift away from more druggable enzyme and GPCR targets has resulted in the development of larger molecules that have physicochemical properties that far exceed those previously expected to yield adequate solubility and permeability for oral absorption. Due to frequently lower solubility and permeability, conducting drug discovery research in bRo5 chemical space is difficult and represents a challenge for medicinal chemists to move away from the more well-understood Ro5 chemical space. In this article, we review the current state of the art for drug discovery bRo5 including a review of the literature, an analysis of physicochemical properties and case studies of the approved classes of bRo5 drugs.