We herein review the state of knowledge regarding the in vitro and in vivo susceptibility of archaea to antimicrobial agents, including some new molecules. Indeed, some archaea colonizing the human microbiota have been implicated in diseases such as periodontopathy. Archaea are characterized by their broad-spectrum resistance to antimicrobial agents. In particular, their cell wall lacks peptidoglycan, making them resistant to antimicrobial agents interfering with peptidoglycan biosynthesis. Archaea are, however, susceptible to the protein synthesis inhibitor fusidic acid and imidazole derivatives. Also, squalamine, an antimicrobial agent acting on the cell wall, proved effective against human methanogenic archaea. In vitro susceptibility data could be used to design protocols for the decontamination of complex microbiota and the selective isolation of archaea in anaerobic culture.