The invention relates to imaging systems that include a coded aperture detection system and an optical detection system. The coded aperture detection system is configured to detect radiation emitted by a radionuclide present within an object and to provide a first detector signal from the detected radiation. The optical detection system is configured to detect optical radiation from the object and to provide a second detector signal from the detected optical radiation. The system also includes a processor configured to prepare first image data from the first detector signal, second image data from the second detector signal, and registered data indicative of a spatial relationship in at least one dimension between the first and second image data. The invention also includes methods of using the new systems, e.g., for sentinel lymph node mapping and tissue resection.