The work presented in this thesis concerns a sub-family of the biologically important family of G-protein coupled receptors (GPCRs) known as histamine receptors. They are recognized as important drug targets for many disorders in mankind, such as allergic rhinitis and Alzheimer’s disease. This thesis has its roots in the first structure of histamine receptor H1, determined in complex with a first generation antihistamine (doxepin) in 2011. Here, extensive biological, computational and structural investigations have been carried out for H1 in complex with two second-generation antihistamines (cetirizine and fexofenadine). Crystal structures of H1-cetirizine (3.1 Å) and H1-fexofenadine (3.4 Å) show the binding modes of second-generation antihistamines correspond well with the previous docking studies. The so-called “anion binding site” on H1 is responsible for the high specificity of the ligands. Some regions on the receptor were difficult to define in the crystal structures. These regions were characterized by radioligand binding assays, together with molecular dynamic simulations (carried out by our collaborators from Oxford University) suggested that, second generation ligands have a significantly large impact on receptor dynamics. While H1 mediates many immune-related disorders, the histamine receptor H3 is a drug target to many mental disorders. In addition to the H1 work presented here, it is also reported the initial work done on the histamine receptor H3. With extensive screenings on various H3 constructs (from human and turkey organisms) and expression systems, it was observed that the best construct was from turkey. An optimal expression protocol in insect cells was obtained. This has established a secure starting point for future structural studies on H3.