The right-handed double-helical structure of DNA (B-DNA), which follows the Watson-Crick model, is the canonical form of DNA existing in normal physiological settings. Even though an alternative left-handed structure of DNA (Z-DNA) was discovered in the late 1970s, Z-form nucleic acid has not received much attention from biologists, because it is extremely unstable under physiological conditions, has an ill-defined mechanism of its formation, and has obscure biological functions. The debate about the physiological relevance of Z-DNA was settled only after a class of proteins was found to potentially recognize the Z-form architecture of DNA. Interestingly, these Z-DNA binding proteins can bind not only the left-handed form of DNA but also the equivalent structure of RNA (Z-RNA). The Z-DNA/RNA binding proteins present from viruses to humans function as important regulators of biological processes. In particular, the proteins ADAR1 and ZBP1 are currently being extensively re-evaluated in the field to understand potential roles of the noncanonical Z-conformation of nucleic acids in host immune responses and human disease. Despite a growing body of evidence supporting the biological importance of Z-DNA/RNA, there remain many unanswered principal questions, such as when Z-form nucleic acids arise and how they signal to downstream pathways. Understanding Z-DNA/RNA and the sensors in different pathophysiological conditions will widen our view on the regulation of immune responses and open a new door of opportunity to develop novel types of immunomodulatory therapeutic possibilities.