This FOA is issued by the National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health. This FOA is a follow up of a previous Roadmap RFA (RM-04-021 “Innovation in Molecular Imaging Probes”). The purpose of this initiative is to encourage the development of novel molecular imaging approaches that can detect and image specific molecular activities in vivo, and have the potential for clinical applications. Novel molecular imaging approaches developed through this initiative can focus on one (or both) of the following long-term translational goals: (1) imaging the characteristic markers, and function, of normal cells in control human subjects and patients, and (2) imaging the characteristic markers, and biochemical or physiological abnormalities, of disease cells in patients. Potential abnormalities that could provide early markers for disease include (but are not restricted to): inflammation, fibrosis, immune cell activation, altered signal transduction pathways, altered gene expression pathways, and altered post-translational modification of proteins. This initiative solicits applications that explore innovative “high-impact” approaches, rather than incremental technology development that is already supported by current NIH programs.