The important insights yielded by molecular imaging (MI) into relevant biologic signatures at an organ-specific and systemic level are not achievable with conventional imaging methods and thus provide an essential link between preclinical and clinical research. New diagnostic probes and imaging methods revealing comprehensive functional and molecular information are being provided by MI research, several of which have found their way into clinical application. However, there are also reservations about the impact of MI and its added value over conventional, often less expensive, diagnostic imaging methods. This perspective discusses seminal research directions for the MI field that have the potential to result in added value to the patient. Emphasis is placed on MI without probes, MI based on radiotracers and small molecules, MI nano- and microsystems, and MI in context with comprehensive diagnostics. Furthermore, besides technical innovations and probes, emerging clinical indications are highlighted.