Cancer when detected at an early stage, before it has spread, can often be treated successfully by surgery or local irradiation. However, when cancer is detected only after it has metastasized, treatments are much less successful.The lymphatic system is a primary path by which malignant cells can travel to other organs in the body. Thus determination of the presence or absence of malignant cells in lymph nodes to which a primary tumor drains is a key component of cancer staging. Sentinel lymph node biopsy (SLNB) has been developed over the past decade as a minimally invasive technique to assess regional lymph node status in patients with malignancy.Despite its routine role in clinical management of cancer, SLNB has a higher false-negative rate (5-10%) than is generally recognized. The current standard of care in SLNB employs a non-imaging gamma probe to locate and excise the sentinel nodes. We are exploring whether the use of a 3-D intraoperative imaging system using a hand held gamma camera could provide advantages compared to the use of the non-imaging probe. The 3-D intraoperative system has been developed through a collaborative effort involving UVa, Dilon Technologies Inc. (Newport News, Virginia), the Jefferson Lab (Newport News, VA) and SurgicEye, (München, Germany). iv The system's hand held camera has a circular field of view (FOV) of diameter 60 mm and comprises a pixelated NaI(Tl) crystal array coupled to an array of silicon photomultipliers (SiPMs). In 3-D operation an optical tracking system consisting of both visual and infrared (IR) cameras tracks the location and orientation of the camera as it is moved by the surgeon. A fast iterative reconstruction algorithm uses the streamed camera data to produce and display the image of the nodes.This thesis evaluates the 2-D and 3-D imaging performance of the hand held gamma camera system. Performance metrics include energy resolution, 2D and 3D spatial resolution, gamma ray detection sensitivity, geometric linearity, attenuation compensation, activity quantification accuracy, and the effect of scatter radiation from the radiotracer injection site.Chapter 1 gives an overview of the current practices of sentinel lymph node biopsy and the various intra-operative surgical guidance modalities that can be used for assistance in the detection of sentinel lymph nodes. This chapter also throws light on some of the drawbacks associated with each of the modalities. Chapter 2 gives a summary of some of the contemporary small gamma cameras that have been developed and used for the detection of cancerous masses and lesions. It also introduces the declipseSPECT system with v the gamma probe and the gamma camera, which forms the crux of this thesis.Chapter 3 gives a detailed explanation of the performance evaluation experiments that were carried out using this novel gamma camera. Chapter 4 concludes this thesis, summarizing the results and comparing them with the other small gamma cameras. Chapter 5 briefly discusses the clinical studies planned with the hand held...