The druggability and developability space is rapidly evolving in the post-genomic era. In the past, Lipinski’s rule-of-five (Ro5) emerged and served as a guide for drug-like molecule design for oral delivery in the traditional druggable target space. In contrast, in this new era, a transition is occurring in drug discovery towards novel approaches to bind and modulate challenging biological targets that have led to transformative treatments for patients. Consequently, drugging novel targets using a variety of emerging molecular modalities, namely beyond the Ro5 (bRo5) small molecules (such as protein-protein interaction modulators, protein-targeted chimeras, or PROTACs), peptide/peptidomimetics, and nucleic acid-based modalities, have become a key focus in drug discovery. Herein, the emerging druggability and developability space is discussed side by side to build a general understanding of the potential development challenges of these novel modalities. An overview is provided on the evolving novel targets and molecular modalities, followed by a detailed analysis of the druggability aspects as well as the strategies used to progress drug candidate, and the trending chemistry and formulation strategies used to assess developability.