The yeast S. cerevisiae was the model organism used during the two-hybrid technique's inception. It is commonly known as the Y2H system. It has several characteristics that make it a robust organism to host the interaction, including the ability to form tertiary protein structures, neutral internal pH, enhanced ability to form disulfide bonds and reduced-state glutathione among other cytosolic buffer factors, to maintain a hospitable internal environment. The yeast model can be manipulated through non-molecular techniques and its complete genome sequence is known. Yeast systems are tolerant of diverse culture conditions and harsh chemicals that could not be applied to mammalian tissue cultures.
A number of yeast strains have been created specifically for Y2H screens, e.g. Y187 and AH109, both produced by Clontech.  Yeast strains R2HMet and BK100 have also been used.