Near Infrared Fluorescence (NIRF) molecular imaging is widely used in research and increasingly employed in the clinic for intraoperative imaging to assist in tumor resection and avoiding critical structures. However, emerging data indicate that it may also find use in early stage diagnosis for diseases such as breast cancer and rheumatoid arthritis. The potential of NIRF probes to provide both molecular and spatial information using non-ionizing radiation in a fast and inexpensive format for clinical diagnosis has significant advantages over blood tests, anatomical and physiological imaging modalities (e.g. MRI, ultrasound), and nuclear medicine. Recently, we have published papers showing oral delivery and subcutaneous injection of NIRF probes are feasible in animal models of breast cancer and rheumatoid arthritis. These routes of administration are less expensive and potentially safer than intravenous delivery, further lowering the barrier to implementation. Despite the potential of self-administered diagnostic probes, there are several challenges before this approach could be broadly applied in the clinic. The principal challenge is depth of imaging, limiting applications to disease sites near an accessible body surface. Additional challenges include the selection of biomarkers to improve diagnosis over current practice and identifying targeting ligands suitable for less-invasive delivery. In this work, we discuss the challenges associated with delivering NIRF molecular imaging agents by oral and subcutaneous injection for the early or subclinical diagnosis of rheumatoid arthritis. We outline a strategy for multiple probes that could provide complementary information and describe how optical advances could further improve the resolution for more accurate diagnosis.