Oncology clinical trials are undergoing transformation to evaluate targeted therapies addressing a wider variety of biologically defined cancer subgroups. Multiarm basket and umbrella trials conducted under master protocols have become more prominent mechanisms for the clinical evaluation of promising new biologically driven anticancer therapies that are integral to precision oncology medicine. These new trial designs permit efficient clinical evaluation of multiple therapies in a variety of histologically and biologically defined cancers. These complex trials require extensive planning and attention to many factors, including choice of biomarker assay platform, mechanism for processing clinicopathologic and biomarker data to assign patients to substudies, and statistical design, monitoring, and analysis of substudies. Trial teams have expanded to include expertise in the interface between biology, clinical oncology, bioinformatics, and statistics. Strategies for the design, conduct, and analysis of these complex trials will continue to evolve to meet new challenges and opportunities in precision oncology medicine.