Methods that can rapidly and specifically analyze nucleic acid sequences will revolutionize the diagnosis and treatment of disease by allowing molecular-level information to be used during routine medicine. In this Perspective, we discuss chemistry-driven approaches that will make the detection of DNA and RNA sequences more routine in clinical settings. In addition, we discuss unmet needs and areas where future effort is necessary to enable nucleic acids analysis to become a mainstream tool in routine clinical medicine. Methods for next-generation sequencing of DNA are producing a wealth of information by allowing the study of how specific genetic mutations or single nucleotide polymorphisms influence the onset of disease, prognosis, or response to treatment. To give this information clinical utility, new methods of detecting nucleic acid sequences are being developed in order to rapidly obtain genetic information in more streamlined formats, and with the ability to obtain information outside of a laboratory setting. Challenges remain in this area, however, and new chemistries that will facilitate fast, simple nucleic acids analysis in a clinical setting are needed.