Advances in next-generation sequencing technologies have generated the data supporting a large volume of somatic alterations in several national and international cancer genome projects, such as The Cancer Genome Atlas and the International Cancer Genome Consortium. These cancer genomics data have facilitated the revolution of a novel oncology drug discovery paradigm from candidate target or gene studies toward targeting clinically relevant driver mutations or molecular features for precision cancer therapy. This focuses on identifying the most appropriately targeted therapy to an individual patient harboring a particularly genetic profile or molecular feature. However, traditional experimental approaches that are used to develop new chemical entities for targeting the clinically relevant driver mutations are costly and high-risk. Drug repositioning, also known as drug repurposing, re-tasking or re-profiling, has been demonstrated as a promising strategy for drug discovery and development. Recently, computational techniques and methods have been proposed for oncology drug repositioning and identifying pharmacogenomics biomarkers, but overall progress remains to be seen. In this review, we focus on introducing new developments and advances of the individualized network-based drug repositioning approaches by targeting the clinically relevant driver events or molecular features derived from cancer panomics data for the development of precision oncology drug therapies (e.g. one-person trials) to fully realize the promise of precision medicine. We discuss several potential challenges (e.g. tumor heterogeneity and cancer subclones) for precision oncology. Finally, we highlight several new directions for the precision oncology drug discovery via biotherapies (e.g. gene therapy and immunotherapy) that target the undruggable cancer genome in the functional genomics era.