Recent advances in tumor biology and human genetics along with the development of drugs for specific targets hold promise for an era of personalized oncology treatment. Routine use of modern technologies, such as large-scale genome sequencing, will help to unravel the specific biology of each tumor. Adding a rigorous genomic view could determine key genetic events, critical dependencies, and stratification of patients in early clinical trials. Integrating biomarker development into the early testing of novel agents might provide clinically relevant therapeutic opportunities for patients with advanced-stage cancer and also accelerate the drug-approval process. After recent success stories of therapies targeting driver molecular aberrations in genetically defined tumor subtypes, innovative clinical trials based on a strong biologic hypothesis are expected to bring further excitement to the field. In this article, we describe a new trend in biomarker-driven early drug development using enrichment and prescreening strategies. Technical and logistical obstacles that may hinder progress of this approach will be discussed, along with ethical and economic concerns.