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Simple Summary Cancer is one of the main causes of death worldwide and early detection is crucial for effective treatment. Scientists have therefore focused on the identification of circulating cancer-specific molecules, so-called markers, that can be detected with non- or less-invasive techniques. One attractive emerging marker is represented by circulating antibodies against molecules that are specific for the tumor cells and not produced by normal cells. Many such auto-antibodies have been discovered, but still not much is known about their significance and role in either promoting or inhibiting tumor growth. The aim of this review is to summarize the current knowledge on auto-antibodies in different cancer types and on their current or possible utilization for effective cancer management. Reference to autoimmune diseases will also be made, as they share with cancer the presence of such auto-antibodies. Abstract Auto-antibodies are classically associated with autoimmune diseases, where they are an integral part of diagnostic panels. However, recent evidence is accumulating on the presence of auto-antibodies against single or selected panels of auto-antigens in many types of cancer. Auto-antibodies might initially represent an epiphenomenon derived from the inflammatory environment induced by the tumor. However, their effect on tumor evolution can be crucial, as is discussed in this paper. It has been demonstrated that some of these auto-antibodies can be used for early detection and cancer staging, as well as for monitoring of cancer regression during treatment and follow up. Interestingly, certain auto-antibodies were found to promote cancer progression and metastasis, while others contribute to the body’s defense against it. Moreover, auto-antibodies are of a polyclonal nature, which means that often several antibodies are involved in the response to a single tumor antigen. Dissection of these antibody specificities is now possible, allowing their identification at the genetic, structural, and epitope levels. In this review, we report the evidence available on the presence of auto-antibodies in the main cancer types and discuss some of the open issues that still need to be addressed by the research community.