Chemically inducible RNA interference (RNAi) enables temporal and/or spatial control of virtually any gene, making it useful for study of gene functions, discovery of potential drug targets, and gene therapy applications. Here we describe a new inducible RNAi platform in which orthogonal chemically modified oligonucleotides are used to trigger silencing of two genes in a combinatorial manner. We developed a modular RNA architecture consisting of an oligonucleotide sensor stem-loop and an RNAi effector domain that is designed to undergo a structural shift upon addition of an oligonucleotide inducer. The induced structural change allows the RNA to be processed by the RNAi machinery, ultimately resulting in gene silencing of the target encoded by the RNAi effector module. Combinatorial regulation of multiple genes should accelerate studies of complex gene-gene interactions and screening of new drug targets.