A majority of primary tumors are detectable early, removable via surgery, or treatable with chemotherapy. However, tumor recurrence, metastasis, and chemoresistance are significant causes of mortality in many tumor types. Like any other organ in the body, tumors harbor cancer stem cells, capable of regenerating the tumor or allowing it to escape a chemotherapy insult. Cancer stem cells are also responsible for aggressive metastasis and chemoresistance. Typical to organogenesis and regeneration, tumors actively recruit supporting stromal cells, bypass immune targeting, and recur and metastasize by harnessing microenvironmental cues. Within this context, how cancer stem cells evade immune suppression and metastasize is of significant interest. Unpacking this interaction will lead to the development of new targeted and immunotherapies to curb metastatic spread and its associated mortality. Here, we will look through a biomedical engineer’s lens to identify variables within the cancer stem cell/immune axis, construct engineered models to isolate the variable and further our understanding of how cancers metastasize.