Non-functioning pituitary adenomas (NFPAs) comprise silent tumors of different pituitary lineages that tend to escape early detection and present as invasive macroadenomas with symptoms of mass effect. Incomplete surgical resection is common and may be followed by significant rates of subsequent remnant progression. Pituitary tumors are defined as refractory when resistance to optimal standard therapies including surgery, radiotherapy, and medical treatment is documented. In the absence of approved medications for the treatment of NFPAs, the last criterion to classify these tumors as refractory is ill defined. Silent corticotroph and null cell adenomas have been reported, albeit not in all studies, to be larger and recur more often compared with silent gonadotroph tumors. Nevertheless, it is currently unknown if certain NFPA subtypes are more often refractory using well defined criteria. The response rate to temozolomide is lower in NFPA compared to that seen in functioning tumors. Refractory NFPAs present a significant diagnostic and therapeutic challenge and are associated with increased morbidity and mortality rates.