DNA and RNA of both natural and synthetic origin can elicit strong immune responses in higher organisms. Computer-aided design in conjunction with high-throughput sequencing has improved our ability to build tuneable synthetic DNA and RNA architectures with high structural and functional precision. The natural biological roles of nucleic acids endow these synthetic assemblies with the ability to specifically engage cellular components. This makes DNA and RNA particularly powerful materials with which to probe or programme immune cells. In this Perspective, we discuss the potential of designer nucleic acid assemblies to control and modulate the immune response for biomedical applications.