Comorbid chronic diseases affect cancer patients with an increasing frequency as populations get older. They negatively and disproportionately impact underserved populations and influence cancer diagnosis, tumor biology and metastasis, and choice of treatment. Many comorbidities are associated with a delayed cancer diagnosis. Although the relationship between comorbidities and cancer risk and survivorship has been studied extensively, we still lack knowledge on how they affect tumor biology and the metastatic process. Here, we will discuss our current understanding of mechanisms linking comorbidities to an adverse tumor biology and lethality and introduce thoughts of how we can close existing gaps in this knowledge. We argue that research into comorbidity-induced alterations in cancer metastasis, immunity, and metabolism should be prioritized.