Thermostability may be engineered in a non-thermostable protein either by protein design, based on known 3D structures, or by directed evolution involving the generation of huge randomized protein variant libraries followed by a great screening and cost efforts involving robotic devices. Alternative genetic selection methods in a thermophile have been described to facilitate the screening. The protein folding interference selection method relies on the use of a folding reporter, a protein conferring a detectable property such as resistance to antibiotics or fluorescence when properly folded. When the reporter is expressed in a thermophile as C-terminal fusion to a target enzyme, only those enzyme variants of a library that are able to fold properly at its high temperature of growth could allow the folding of the reporter, which in turns confers the detectable property. In contrast, the natural enzyme and most of the randomized variants will be unable to fold at high temperature and block (interfere) the folding of the reporter. Reporters conferring thermostable resistances to antibiotics have been used for the selection of thermostable variants of therapeutic proteins and enzymes (Chautard et al 2007), but always using living T. therophilus cells as expression hosts (in vivo selection). For in vitro selection, the HotDrops platforms is aimed to use in vitro transcription-translation systems derived from T. thermophilus in combination with thermostable fluorescent proteins as reporters.