Head and neck squamous cell carcinomas (HNSCCs) are cancers that arise in the upperaerodigestive tract mucosa. The five-year patient survival rate is ~50% and current treatments are associated with severe morbidities. New molecular targets and therapies must be identified to improve outcomes for HNSCC patients. Bitter taste receptors (T2Rs) are a family of G-protein coupled receptors (GPCRs). When activated by bitter agonists, T2Rs mobilize intracellular calcium (Ca2+). Here, I uncover that bitter taste receptor isoform 14 (T2R14) is an attractive anti- cancer target in HNSCC. I discovered that lidocaine, a local anesthetic, mobilizes intracellular Ca2+ mobilization by activating T2R14 in HNSCC cells. Furthermore, T2R14 activation with lidocaine depolarizes mitochondria, inhibits proliferation and proteasome function, and induces apoptosis. The Cancer Genome Atlas (TCGA) revealed that HPV-associated (HPV+) HNSCCs are associated with increased TAS2R14 expression. Lidocaine treatment may benefit these patients, warranting future clinical studies. Furthermore, I investigated GLUT1 (SLC2A1), a facilitated-diffusion glucose transporter, as an additional target to enhance the apoptotic effects of lidocaine and other bitter agonists. Examination of immortalized HNSCC cells, patient samples, and TCGA revealed high expression of GLUT1. A recently developed small molecule inhibitor of GLUT1, BAY-876, induced apoptosis in HNSCC cells. BAY-876 enhanced the apoptotic effects when combined at low concentrations with bitter agonists, including lidocaine. Targeting GLUT1 via BAY-876 to kill HNSCC cells in combination with T2R14 agonists is a potential novel treatment strategy. Beyond exogenous activation, T2R14 may also function in the HNSCC tumor microenvironment (TME). N-3-oxo-dodecanoyl-L-acylhomoserine lactone (3-oxo-C12HSL) is a quorum-sensing N-acyl homoserine lactone (AHL) secreted by Pseudomonas aeruginosa, a microbe present in the HNSCC TME. Like lidocaine, 3-oxo-C12HSL activated intracellular Ca2+ responses in HNSCC cells through T2R14. 3-oxo-C12HSL inhibited cell viability, depolarized mitochondria, produced ROS, and induced apoptosis in HNSCC cells. P. aeruginosa may play a significant role in modulating an anti-tumor TME through 3-oxo-C12HSL-T2R14 activation. Data here suggest that T2R14 could serve as a therapeutic target and may be implicated in HNSCC TME biology. Further research is warranted to translate T2R14 bitter agonist therapies into the clinic and to investigate T2R14 in other cancers.