A new group of thermoelectric materials, trigonal and tetragonal XYZ_2 (X, Y: rare earth or transition metals, Z: group VI elements), the prototype of which is TmAgTe_2, is identified by means of high-throughput computational screening and experiment. Based on density functional theory calculations, this group of materials is predicted to attain high zT (i.e. ∼1.8 for p-type trigonal TmAgTe_2 at 600 K). Among approximately 500 chemical variants of XYZ_2 explored, many candidates with good stability and favorable electronic band structures (with high band degeneracy leading to high power factor) are presented. Trigonal TmAgTe_2 has been synthesized and exhibits an extremely low measured thermal conductivity of 0.2–0.3 W m^(−1) K^(−1) for T > 600 K. The zT value achieved thus far for p-type trigonal TmAgTe_2 is approximately 0.35, and is limited by a low hole concentration (∼10^(17) cm^(−3) at room temperature). Defect calculations indicate that Tm_(Ag) antisite defects are very likely to form and act as hole killers. Further defect engineering to reduce such XY antisites is deemed important to optimize the zT value of the p-type TmAgTe_2.