Provide concise and practice observations of dealing with high-risk cutaneous squamous cell carcinoma regarding the implementation of sentinel node biopsy technique based on scientific data. Skin cancer occurs mostly in head and neck sites. It varies and is influenced by geographic location, with higher rates at lower latitudes and a lifetime risk of 9% to 14% among men and 4% to 9% among women. Its lifetime risk is increasing worldwide with an increasing incidence of 50% to 300% in the last three decades and 250,000 diagnosed annually in the United States. Despite most of them with a good prognosis, high-risk features led to a dismal prognosis. It spreads preferably by lymphatic vessels to lymph nodes, but controversy remains about the best means to determine which patients have lymphatic metastases and which lymph nodes are affected. Clinical examination and radiological techniques had approximately 30% false negatives and false positives rates in determining whether there are cervical lymphatic metastases. The only precise method for neck staging is the histopathological examination of the surgical specimen after neck dissection. Lymphatic drainage for skin cancer could be anomalous, and metastases in lymph nodes imply decreasing survival of even 50%. The rate of occult lymphatic metastases could be even 29.8% in high-risk features. Using minimally invasive techniques is possible to select patients for a better staging strategy. Preoperative lymphoscintigraphy and intraoperative gamma probe help in the localization of radioactive sentinel nodes that may contain microscopic tumor deposits. It is improbable that patients without palpable lymph node disease and metastatic disease-free sentinel node have metastatic disease in non-sentinel nodes in melanoma studies. We will highlight the patient selection criteria, technical notes, and main work-up with special consideration related to the nuclear medicine partnership.