Refractory types of glaucoma continue to present a therapeutic challenge to ophthalmologists. Approaches toward the management of these difficult glaucomas are addressed in this paper. The first part devotes special attention to understand the cause(s) of the failure of previous filtering surgery(ies). The next part emphasizes filtration surgery with intraoperative application of antimetabolites: 5-fluorouracil or mitomycin C and the surgical and pharmacological management of failing filtration. In case of failure of multiple filtering surgery with application of antimetabolites, surgeons have to consider cyclodestructive procedures (transscleral diode laser or endoscopic cyclophotocoagulation) to reduce aqueous production, or fistulizing procedures with tube implants or other drainage devices (valves).