This article evaluates the probable causes of seismicity in the Texas and Oklahoma Panhandle region, including reviewing historical earthquakes with magnitudes of 3.9–5.4 reported between 1917 and 1980 and more recent earthquakes recorded by stations in the EarthScope Transportable Array (TA) between 2008 and 2011. We believe this is the first scientific publication focusing primarily on Panhandle earthquake activity since a 1939 technical report describing the 5.0 Panhandle earthquake of 1936. Historical earthquakes in 1936, 1966, 1974 and 1980 occurred within or at the boundary of highly productive petroleum fields, and may have been induced by production; however, this conclusion is highly ambiguous because the locations are poorly determined, information about focal depths is absent, and we have only limited information about the petroleum production. We evaluated EarthScope TA data using routine network processing and augmented those detection methods with waveform template matching to identify 374 earthquakes. Most of the detected earthquakes occurred in an east–west band extending across the Texas Panhandle between 35.25° and 36.25° N, coinciding approximately with fault systems associated with the Amarillo‐Wichita uplift. Analysis of these data suggests that there are naturally occurring earthquakes in the Texas and Oklahoma Panhandles as well as a few examples of earthquakes possibly induced by production, by wastewater injection, or by hydraulic fracturing. In selected areas, future seismic deployments with station separations of a few kilometers could determine accurate focal depths for Panhandle earthquakes, making it possible to better assess whether observed events were natural or induced.