We study a family of unbounded Hermitian operators in Hilbert space which generalize the usual graph-theoretic discrete Laplacian. For an infinite discrete set X, we consider operators acting on Hilbert spaces of functions on X, and their representations as infinite matrices; the focus is on l(2)(X), and the energy space H-epsilon. In particular, we prove that these operators are always essentially self-adjoint on l(2)(X), but may fail to be essentially self-adjoint on H-epsilon. In the general case, we examine the von Neumann deficiency indices of these operators and explore their relevance in mathematical physics. Finally we study the spectra of the H-epsilon operators with the use of a new approximation scheme. (C) 2011 Elsevier Inc. All rights reserved.