Nitrogen (N) is an essential macronutrient for plants, and a major limiting factor for plant growth and crop production. Nitrate is the main source of N available for plants in agricultural soils and in many natural environments. Sustaining agricultural productivity is of paramount importance in the current scenario of increasing world population, diversification of crop uses, and climate change. Plant productivity for major crops around the world is still supported by excess application of N-based fertilizers with detrimental economic and environmental impacts. Thus, understanding how plants regulate nitrate uptake and metabolism is key for developing new crops with enhanced N use efficiency (NUE) and to cope with future world food demands. The study of plant responses to nitrate has gained considerable interest over the last thirty years. This review provides an overview of key findings in nitrate research, spanning biochemistry, molecular genetics, genomics and systems biology. We discuss how we reached our current understanding of nitrate transport, local and systemic nitrate sensing/signaling, and the regulatory networks underlying nitrate-controlled outputs in plants. We hope this summary serves not only as a time-line and information repository, but also as a base to outline important open questions for future research.