Content-based image retrieval (CBIR) is a promising technology to enrich the core functionality of picture archiving and communication systems (PACS). CBIR has a potentially strong impact in diagnostics, research, and education. Research successes that are increasingly reported in the scientific literature, however, have not made significant inroads as medical CBIR applications incorporated into routine clinical medicine or medical research. The cause is often attributed without sufficient analytical reasoning to the inability of these applications in overcoming the semantic gap. The semantic gap divides the high-level scene analysis of humans from the low-level pixel analysis of computers. In this paper, we suggest a more systematic and comprehensive view on the concept of gaps in medical CBIR research. In particular, we define a total of 13 gaps that address the image content and features, as well as the system performance and usability. In addition to these gaps, we identify 6 system characteristics that impact CBIR applicability and performance. The framework we have created can be used a posteriori to compare medical CBIR systems and approaches for specific biomedical image domains and goals and a priori during the design phase of a medical CBIR application. To illustrate the a posteriori use of our conceptual system, we apply it, initially, to the classification of three medical CBIR implementations: the content-based PACS approach (cbPACS), the medical GNU image finding tool (medGIFT), and the image retrieval in medical applications (IRMA) project. We show that systematic analysis of gaps provides detailed insight in system comparison and helps to direct future research.