The genesis of this theme issue and the meeting around which it is based, was a conversation on the way to the opening reception at the AAPS annual meeting in San Diego 2014. In it we started to discuss the challenges of beyond-rule-of-5 (bRo5) compounds and to what extent we could expect oral administration to provide a viable means to support therapeutic concentrations of such molecules. The central point of the discussion was the argument that the reason for compounds ending up in the bRo5 space was biological and that target biology would dictate the molecular properties of the ligand. Thus, for targets with highly lipophilic binding pockets or targets directed to broad protein-protein interactions where large, flat binding pockets are common, it was highly unlikely that ligands could be identified that were Ro5 compliant. Against this backdrop, it seemed likely that bRo5 compounds would persist, and if anything become more prevalent, and therefore that as delivery scientists we needed to recalibrate our views as to how to enable their oral delivery. For example, what zones in the bRo5 chemical space are actually orally tractable and how can we identify them? To what extent do we understand the molecular characteristics of bRo5 compounds that may be orally bioavailable? How do we make use of this information to identify, early in development, compounds in this chemical space that are sufficiently drug-like to be translated into well-functioning oral medicines? What is the state-of-the-art in delivery technologies to help support oral absorption for these challenging molecules? As we walked, we realized we had many more questions than answers and so the discussions began that led to the 49th Journées Galéniques de St. Rémy de Provence meeting in June 2015 and the collection of reviews that comprise this theme issue - the latter based largely (but not exclusively) around the St. Rémy meeting.