This dissertation considers the problem of reasoning about irrelevance of knowledge in a principled and efficient manner. Specifically, it is concerned with two key problems: (1) developing algorithms for automatically deciding what parts of a knowledge base are irrelevant to a query and (2) the utility of relevance reasoning. The dissertation describes a novel tool, the query-tree, for reasoning about irrelevance. Based on the query-tree, we develop several algorithms for deciding what formulas are irrelevant to a query. Our general framework sheds new light on the problem of detecting independence of queries from updates. We present new results that significantly extend previous work in this area. The framework also provides a setting in which to investigate the connection between the notion of irrelevance and the creation of abstractions. We propose a new approach to research on reasoning with abstractions, in which we investigate the properties of an abstraction by considering the irrelevance claims on which it is based. We demonstrate the potential of the approach for the cases of abstraction of predicates and projection of predicate arguments. Finally, we describe an application of relevance reasoning to the domain of modeling physical devices.