What is the Universe made of? This question is the longest outstanding problem in all of modern physics and the hottest research topic in cosmology and particle physics today. The talk begins with an overview of the history of the problem, including the evidence for the existence of dark matter in galaxies. Then I will turn to the big picture of the Cosmos: the Universe is made of 5% ordinary atomic matter, 26% dark matter, and 69% dark energy. I will discuss the conundrum of the nature of the dark matter and discuss the best-motivated particle candidates. Dark matter searches are three-pronged: at the particle accelerator known as the Large Hadron Collider at CERN in Geneva; in the underground laboratory experiments worldwide; and with satellites in space and phototubes in the ice at the South Pole searching for signals of dark matter annihilation products. Currently there are claimed detections in multiple experiments --- but they cannot possibly all be right. Excitement is building in the cosmology community that the nature of the dark matter particle may soon be revealed. I conclude the talk with the question of the unanticipated dark energy that is causing the Universe's expansion to accelerate and its effect on the future fate of life in the Universe.