A diverse spectrum of pathogens and pests has been identified to infest various plant species and cause havoc on horticultural, agricultural, and forestry crops. Several improved crop varieties that are resistant to a variety of plant diseases brought on by biotic (pests, pathogens) and/or abiotic (climate change) factors are the main focus of plant biotechnologists across the world. Although numerous conventional methods might potentially minimize agricultural production loss; improved, cost-effective, ecologically sound, and efficacious solutions are required to fulfill the needs of a rising population. Thus, RNA interference (RNAi) finds paramount importance in resolving many hazardous plant diseases. RNAi is a method of gene silencing that uses double-stranded RNA of both plants and animals as triggers and targets homologous RNA to degrade or inhibit gene expression at the transcriptional, translational level in a sequence-specific manner or by chromatin remodeling. siRNA and miRNA are the two types of small single-stranded RNAs that play a significant role in the RNAi pathways. Recently several transgenic and non-transgenic plant-based RNAi techniques have been proven to have great potential in treating plant diseases when no other alternatives were available. Therefore RNAi is considered to serve as a novel gene therapy technique for plant disease control and management. In this chapter, an attempt has been made to elucidate the development of RNA interference, the molecular mechanism underlying this technique, and various strategies and applications to effectively control plant diseases through a pest management approach.