Minimally invasive molecular biomarkers have been applied to the early detection of multiple cancers in large scale case‐control and cohort studies. These demonstrations of feasibility herald the potential for permanent transformation of current cancer screening paradigms. This commentary discusses the major opportunities and challenges facing the preclinical development and clinical validation of multicancer early detection test strategies. From a diverse set of early detection research perspectives, the authors recommend specific approaches and highlight important questions for future investigation. Minimally invasive, molecular biomarkers demonstrate feasibility for the early detection of multiple cancers in large‐scale case control and cohort studies. Here the paradigm‐changing opportunities and the challenges facing the preclinical development and clinical validation of multicancer early‐detection test strategies are discussed.