Careful observation of cellular processes has revealed exquisite examples of how the architecture of DNA and RNA can confer unique and complex functionality upon nucleic acid sequences. DNA superhelices, tRNA, and other intracellular ribozymes are essential components of life processes which require higher ordered structure for proper function. The realization that higher order nucleic acid architectures can afford unique functionality has ignited a new field of research that attempts to exploit such structures for a vast array of applications. In this chapter, we describe a novel three-dimensional nucleic acid architecture, referred to as the spherical nucleic acid (SNA), which possesses a number of exceptional properties not observed with any other nucleic acid structural motif. We then discuss how the unique properties of SNAs are being exploited in many next generation extra- and intra-cellular diagnostic and therapeutic applications.