Antibodies are specialized proteins generated by immune system for high specificity and affinity binding to target antigens. Because of their essential roles in immune system, antibodies have been successfully developed and engineered as bio-pharmaceuticals for treatment of various diseases. Analysis of antibody-protein interactions is always required to get detailed information on effectivity of such antibody-based therapeutics. Although physicochemical rules cannot be generalized for every antibody-protein interaction, there are some features which should be taken into account during antibody development and engineering efforts. In this chapter, physicochemical analysis of antibody paratope-protein epitope interactions will be discussed to highlight important characteristics. First, paratope and non-paratope regions of antibodies will be described and important roles of these regions on binding and biophysical features of antibodies will be discussed. Then, general features of epitope regions of protein antigens will be introduced along with several computational/experimental tools to identify them. Lastly, a rising star of antibody biopharmaceuticals, nanobodies, will be described to show importance of nextgeneration antibody fragment based biopharmaceuticals in drug development.