Nitrogen (N)-based fertilizers increase agricultural productivity but have detrimental effects on the environment and human health. Research is generating improved understanding of the signaling components plants use to sense N and regulate metabolism, physiology, and growth and development. However, we still need to integrate these regulatory factors into signal transduction pathways and connect them to downstream response pathways. Systems biology approaches facilitate identification of new components and N-regulatory networks linked to other plant processes. A holistic view of plant N nutrition should open avenues to translate this knowledge into effective strategies to improve N-use efficiency and enhance crop production systems for more sustainable agricultural practices.