The description of detailed structural and functional characteristics of the neurokinin 1 receptor (NK-1R) has opened multiple avenues of research into its participation in health and disease. The information has also led to synthesizing antagonists (with high potency and selectivity) ready to be tested to treat many human diseases, such as diverse types of neoplasia, immunological pathologies, and mental disorders. NK-1R is a class A family of G-protein-coupled receptors (GPCRs). It induces intracellular signals through various transducers (Gα, Gβγ, and β-arrestins) from the cell membrane and internalized receptors traveling in endosome vesicles. This versatility and pleiotropy make NK-1R a promising target for therapeutic interventions. In this chapter, we review key features of the structure and activation of NK-1R and analyze its signaling landscape, highlighting the plausible application of NK-1R antagonists as therapeutic agents at the cell surface and intracellularly.