Decades of work by countless astrophysicists have built a quantitative understanding of the composition, history, and fundamental laws of our cosmos. Despite these successes major mysteries remain, among them the nature of the dark matter that forms the foundation of cosmic structure and the physics behind the inflationary epoch that begins our story of the universe. These and other mysteries suggest new fundamental physics waiting to be discovered. I will describe two efforts to probe such fundamental mysteries with novel instrumentation. The first is the quest to directly detect the interactions of dark matter in detectors deep beneath the earth's surface, in particular those of the Cryogenic Dark Matter Search (CDMS). The second is a suite of instruments to observe the imprint of cosmic inflation on the polarization of the cosmic microwave background from vantage points on (BICEP2, Keck) and far above (SPIDER) the Antarctic ice. Each of these instruments employs novel sub-Kelvin instrumentation to achieve the exquisite sensitivity and control of systematic errors needed to push forward the frontiers of these endeavors. I will discuss the status of these instruments and what the future of these programs may hold.