Melanoma is a type of skin cancer that can metastasize in advanced stages to other organs such as the brain, lymph nodes, lungs and liver. Current standard treatment options include surgery, radiation therapy, chemotherapy, and immunotherapy. More recently, oncolytic virotherapy is being studied as a new strategy to fight cancer. Specifically, for melanoma, a herpes virus (T-VEC) was approved by the U.S Food and Drug Administration in 2015 to treat advanced disease. Oncolytic viruses have the capacity to replicate mostly in cancer cells while leaving healthy somatic cells free from infection. Additionally, most of these viruses have the ability to induce an immune response against the cancer as well. Myxoma virus (MYXV) causes myxomatosis in European rabbits but not in any other mammal. In humans, MYXV can infect and kill cancer cells acting as an oncolytic virus. However, the mechanisms behind how myxoma kills cancerous cells are not completely known. To investigate this, we treated melanoma murine cancer cells (B16F10) in vitro with different genetically modified myxoma virus mutants, as well as with a novel second mitochondria-derived activator of caspase mimicking drug SMAC-LCL161, to understand the mechanisms by which MYXV induces cell death. In parallel, B16F10 lacZ cells were subcutaneously injected into mice to engraft melanoma tumors. These tumors were treated with intratumoral injections of different viral mutants or armed viruses derived from MYXV along with SMAC-L61. After a period of treatment, the tumors were isolated. Cell death pathways in both cell culture and in tumors obtained from subcutaneous pathways were identified using different techniques. The study showed an increase in activated caspase 3 and cleaved PARP-1 activity in B16F10 lacZ cells from cell culture when compared to cells in vivo however the two apoptosis markers did not track with each other consistently.