This chapter describes the current status of development of the fragment molecular orbital (FMO) method for analyzing the electronic state and intermolecular interactions of biomolecular systems in solvent. The orbital energies and the inter-fragment interaction energies (IFIEs) for a specific molecular structure can be obtained directly by performing FMO calculations by exposing water molecules and counterions around biomolecular systems. Then, it is necessary to pay attention to the thickness of the water shell surrounding the biomolecules. The single-point calculation for snapshots from MD trajectory does not incorporate the effects of temperature and configurational fluctuation, but the SCIFIE (statistically corrected IFIE) method is proposed as a many-body correlated method that partially compensates for this deficiency. Furthermore, implicit continuous dielectric models have been developed as effective approaches to incorporating the screening effect of the solvent in thermal equilibrium, and we illustrate their usefulness for theoretical evaluation of IFIEs and ligand-binding free energy on the basis of the FMO-PBSA (Poisson–Boltzmann surface area) method and other computational methods.