In the context of other proteomic technologies, targeted antibody arrays are strongly contributing for protein profiling and functional proteomics analyses in serum specimens. Protein-protein interactions, post-translational modifications, and interaction between protein and DNA or RNA can all shift the activity of a protein from what would have been predicted by its level of transcription. Functional proteomics studies the interaction of proteins within their cellular environment to determine how a given protein accomplishes its specific cellular task. Accordingly, the promise of protein profiling and functional proteomics is that by chronicling the function of aberrant or over-expressed proteins, it will be possible to characterize the mechanism of the disease-sustaining proteins. The further understanding of the disease networks will eventually lead to targeted cancer therapy and specific biomarkers for diagnosis, prognosis or therapeutic response prediction based on disease specific proteins. This review describes how such strategies reported to date in serum specimens may assist in characterizing tumor biology, and for the diagnosis, surveillance, prognosis, and potentially for predictive and therapeutic purposes for patients affected with solid and hematological neoplasias.