The lanthanide elements (Lns) affect the physiology and growth of certain microorganisms known as “Ln-responsive microorganisms.” Among them, in 2011, it was first reported that strains of Methylobacterium exhibited high methanol dehydrogenase (MDH) activity when grown in the presence of Lns; the purified Ln-inducible MDH was identified as XoxF-type MDH, whose catalytic function had previously been unknown. XoxF was the first enzyme to be identified as Ln-dependent, and its function in methylotrophy is more fundamental and important than that of the corresponding Ca2 +-dependent MDH MxaFI. XoxF is encoded in the genomes of methylotrophic as well as non-methylotrophic bacteria. Thus, Lns are among the most fascinating and important growth factors for bacteria that potentially utilize methanol. Bacteria that require Lns for methanol growth are called “Ln-dependent methylotrophs.” Recent findings indicate that these microorganisms comprise an “Ln-dependent ecosystem” that we have not been able to reconstruct under laboratory conditions without Lns. In this chapter, we summarize methods for (1) screening of Ln-responsive microorganisms, (2) purification of native XoxFs from Ln-dependent methylotrophs, and (3) screening of Ln-dependent methylotrophs from natural environments, while providing a history of the discovery of the Ln-dependent methylotrophs.