Simple SummaryCaspase-8 is a protease mediating the activation of the extrinsic apoptotic process that leads to programmed cellular death. Evasion of apoptosis is one of the key hallmarks of cancer and Caspase-8 has commonly been associated with an antitumor protective role. However, observations that several solid tumor types inconsistently display aberrantly high levels of Caspase-8 has fueled studies that challenge this dogma. In this review, we summarize the current state of the art on how tumors benefit from high levels of Caspase-8 expression. In addition, we discuss the mechanisms through which tumors are able to alter the function of Caspase-8 and turn a protective protein into an ally. Specifically, we focus on the role played by tyrosine kinases in inhibiting the enzymatic role of Caspase-8 and remodulating Caspase-8 function in cancer through tyrosine phosphorylation.AbstractCaspase-8 is a cysteine-aspartic acid protease that has been identified as an initiator caspase that plays an essential role in the extrinsic apoptotic pathway. Evasion of apoptosis is a hallmark of cancer and Caspase-8 expression is silenced in some tumors, consistent with its central role in apoptosis. However, in the past years, several studies reported an increased expression of Caspase-8 levels in many tumors and consistently identified novel “non-canonical” non-apoptotic functions of Caspase-8 that overall promote cancer progression and sustain therapy resistance. These reports point to the ability of cancer cells to rewire Caspase-8 function in cancer and raise the question of which are the signaling pathways aberrantly activated in cancer that may contribute to the hijack of Caspase-8 activity. In this regard, tyrosine kinases are among the first oncogenes ever identified and genomic, transcriptomic and proteomic studies indeed show that they represent a class of signaling molecules constitutively activated in most of the tumors. Here, we aim to review and discuss the role of Caspase-8 in cancer and its interplay with Src and other tyrosine kinases.