We introduce the notion of pseudo-Hermiticity and show that every Hamiltonian with a real spectrum is pseudo-Hermitian. We point out that all the PT-symmetric non-Hermitian Hamiltonians studied in the literature belong to the class of pseudo-Hermitian Hamiltonians, and argue that the basic structure responsible for the particular spectral properties of these Hamiltonians is their pseudo-Hermiticity. We explore the basic properties of general pseudo-Hermitian Hamiltonians, develop pseudo-supersymmetric quantum mechanics, and study some concrete examples, namely the Hamiltonian of the two-component Wheeler-DeWitt equation for the FRW-models coupled to a real massive scalar field and a class of pseudo-Hermitian Hamiltonians with a real spectrum.