Although the traditional strategy of developing general medical treatments for heterogeneous patient populations has a well-established track record, the acknowledgment that one-size-does-not-fit-all is pushing health-care to enter a new era of tailored interventions. The advent of precision medicine is fueled by the high-throughput analysis of individual DNA variants and mRNA expression profiles. However, due to the role of proteins in providing a more direct view of disease states than genomics alone, the ability to comprehensively analyze protein alterations and post translational modifications (PTMs) is a necessary step to unravel disease mechanisms, develop novel biomarkers and targeted therapies. Protein and peptide microarrays can play a major role in this frame, due to high-throughput, low sample consumption and wide applicability. Here, their current role and potentialities are discussed through the review of some promising applications in the fields of PTMs analysis, enzyme screening, high-content immune-profiling and the phenotyping of extracellular vesicles.