The development of noninvasive screening tests would represent a major advance in the fight against cancer, as pre-clinical or early diagnosis could be considered the best weapons to reduce cancer mortality. The use of autoantibodies against cancer autoantigens is a promising alternative to fulfill this goal. Recent progress in protein microarray formats and other proteomic strategies has brought extraordinary opportunities to advance the discovery of new cancer autoantigens. These new approaches have allowed identification of autoantibodies with a higher prevalence, simplifying the development of predictor panels with wider coverage. Still, some issues have to be resolved before clinical application of these results. First, technical limitations in the quality and reproducibility of the microarrays and the statistical tools for data analysis have to be resolved. Second, thorough validation of the candidate biomarkers has to be carried out to include not just one particular cancer type but different cancers and other benign, inflammatory pathologies, which may give rise to cross-reactions and loss of the specificity and sensitivity of the predictive assay. The extraordinary sensitivity of the immune system to detect minor alterations in self-proteins might be used to highlight changes in the cancer protein sequence and structure that can be used for personalized therapy, including immunotherapeutic vaccines. The increasing detection of kinase proteins as autoantibody targets points to new molecules with potential therapeutic impact.