While protein-protein interaction is the first step of the SARS-CoV-2 infection, recent comparative proteomic profiling enabled the identification of over eleven thousand protein dynamics, thus providing a comprehensive reflection of the molecular mechanisms underlying the cellular system in response to viral infection . Here we summarize and rationalize the results obtained by various mass spectrometry (MS) -based proteomic approaches applied to the functional characterization of proteins and pathways associated with SARS-CoV-2-mediated infections in humans . Comparative analysis of cell-lines vs tissue samples indicates that our knowledge in proteome profile alternation in response to SARS-CoV-2 infection is still incomplete and the tissue-specific response to SARS-CoV-2 infection can probably not be recapitulated efficiently by in vitro experiments . However, regardless of the viral infection period, sample types, and experimental strategies, a thorough cross-comparison of the recently published proteome, phosphoproteome, and interactome datasets led to the identification of a common set of proteins and kinases associated with PI3K-Akt, EGFR, MAPK, Rap1, and AMPK signaling pathways . Ephrin receptor A2 (EPHA2), was identified by 11 studies including all proteomic platforms suggesting as a potential future target for SARS-CoV-2 infection mechanisms and the development of new therapeutic strategies . We further discuss the potentials of future proteomics strategies for identifying prognostic SARS-CoV-2 responsive age, gender-dependent tissue-specific protein targets . This article is protected by copyright . All rights reserved.