One of the great challenges in NIR fluorescence imaging is still its limited capability to penetrate human tissue. None of the above-described studies reported the ability to detect metastases more than 8 mm below the liver capsule. For colorectal liver metastases, however, this technique is very useful, as colorectal liver metastases are mostly located on the surface of liver parenchyma. Deeper localized metastases also show a fluorescent rim after resection and sectioning (Fig. 16.2) [38], but detection of these tumors still needs conventional technologies. Although this is a great limitation, NIR fluorescence imaging also has major advantages. Conventional imaging technologies easily miss superficial liver metastases smaller than 10 mm [7, 9]. In NIR fluorescence imaging, the bright signal enables surgeons to detect lesions as small as 1 mm in real-time (Fig. 16.4) [7, 27]. Indeed, additional, otherwise undetectable metastases were identified in 7 studies [26–28, 30, 32–34]. Van der Vorst et al. report identification of otherwise undetectable liver metastases in 5 of 40 patients (12.5 %, 95 % CI = 5.0–26.6) [27]. Combining contrast-enhanced IOUS and NIR fluorescence imaging together with CT and MRI, Uchhiyama et al. improved diagnostic sensitivity in 32 consecutive patients from 88.5 % to 98.1 % (P=0.050) [33]. Yokoyama et al. showed the potential of using NIR fluorescence imaging by screening the hepatic surface during pancreatic surgery with curative intent [34]. In 49 patients without preoperative detected hepatic metastases, 13 abnormal fluorescent lesions were detected without any apparent tumor, and 8 of them contained micrometastases. Within 6 months after surgery, 10 patients with abnormal fluorescence developed hepatic metastases, versus 1 of 36 patients in the fluorescence negative group, resulting in a positive predictive value of 77 % and a negative predictive value of 97 %. This outcome could possibly help surgeons select patients for either curative or palliative treatment.