Non-melanoma skin cancer (NMSC) is the leading cause of cancer worldwide with an incidence of more than 1 million new cases each year, occurring at a rate of 3% annually. As the incidence of skin cancer continues to rise, it becomes increasingly important to ensure safe and effective ways to manage cutaneous malignancies. Treatment options for NMSC include traditional excision, curettage and electrodessication, cryosurgery, external beam radiation, topical chemotherapeutic agents or Mohs micrographic surgery (MMS). There has been ongoing debate over the past decade about the safety of outpatient surgery, with increasing scrutiny on complications associated with outpatient procedures. Much of the alarm over outpatient-based surgical procedures stems from serious adverse events occurring in patients having procedures performed under general anesthesia in an ambulatory surgical facility. Serious adverse events during and following outpatient based cutaneous surgery, however, are rare. MMS has proven to be effective in the treatment of skin cancer. The cost-effectiveness of MMS has also been well-established. Complications and serious adverse events associated with MMS have been evaluated by single-surgeon studies in both the outpatient clinic and hospital-based settings. Retrospective studies have also examined the safety of MMS. While these studies provide evidence for the safety of the procedure, a prospective, multicenter study would afford a higher level of clinical evidence, and definitively establish the safety profile of MMS and reconstruction in the ambulatory setting. This paper is divided into two sections. In the first section, we report the results of an original, prospective, multi-site research study that evaluated the rate of serious adverse events, post-operative complications, and post-operative pain associated with the treatment of skin cancer using MMS in 1550 patients with 1792 tumors. The study resulted in a complication rate of 2.6% (44/1709), with a breakdown of 21 cases of active bleeding, 2 hematomas, 16 infections, and 5 flap or wound edge necrosis. There were 10 cases of secondary complications. When compared to patients without complications, those who developed a complication were older (73.5±13 vs 69±13, p=0.024), had larger tumors (1.6±1.11 vs 1.12±0.75 cm, p=0.0001), and had larger post-operative defects (2.41±1.52 vs 1.88±1.2 cm, p=0.0032). Furthermore, patients with a complication reported higher mean pain scores than those who did not develop complications (3.08±2.92 vs 1.96±2.38, p=0.0014). In conclusion, MMS is proven as a highly effective, cost-effective, well-tolerated, and extremely safe procedure for the treatment of skin cancer. This prospective, multicenter study helps confirm the high degree of safety of MMS within the United States. In the second section of the paper, we performed a literature search to assess the factors that affect pain levels and the optimal treatment regimen for minimizing post-operative pain in patients after undergoing MMS. In a medical system centered on providing quality of care to patients, we felt that it was equally important to understand factors that influence pain levels in patients in order to ensure patient satisfaction. Our search resulted in only two published articles of original research that were both recently published over the past two years. Overall, the articles found that higher reported pain levels were associated with ages lt; 65 years old, complex repairs (such as grafts and flaps), narcotic use, and cancers of the lip. Interestingly, higher pain levels were not associated with larger defect sizes. Both studies also found that acetaminophen and/or ibuprofen provided adequate pain control for the majority of the patients. Although these results provided interesting conclusions, we were unable to compare absolute pain values due to the use of different outcome measurement tools. Future research in this area should occur in large university academic centers, use standardized outcome measurement tools, and incorporate psychological factors in the assessment of post-operative pain levels.