Historically, cancers have been treated with chemotherapeutics aimed to have profound effects on tumor cells with only limited effects on normal tissue. This approach was followed by the development of small-molecule inhibitors that can target oncogenic pathways critical for the survival of tumor cells. The clinical targeting of these so-called oncogene addictions, however, is in many instances hampered by the outgrowth of resistant clones. More recently, the proper functioning of non-mutated genes has been shown to enhance the survival of many cancers, a phenomenon called non-oncogene addiction. In the current review, we will focus on the distinct non-oncogenic addictions found in cancer cells, including synthetic lethal interactions, the underlying stress phenotypes, and arising therapeutic opportunities.