From the fundamental studies of Louis Pasteur in the XIX century to the current genomic analysis, the essential role of microorganisms in winemaking industry is well recognised. In the last decades, selected Saccharomyces cerevisiae strains with excellent fermentative behaviour have been widely commercialised in form of active dry yeasts. Currently, the production of organic and “natural” wines represents a new economically relevant trend in the wine sector. Based on this market demand, the use of industrial yeast starter could be perceived as non-organic practice and then, rejected. However, in order to preserve wines sensory quality, healthiness, and to avoid organoleptic defects given by undesirable microorganisms, the “yeast factor” (S. cerevisiae or non-Saccharomyces) cannot be ignored. The purpose of this chapter is to describe the methods of selection of wine yeasts focusing the attention on indigenous S. cerevisiae strains. In fact, the use of ecotypic yeasts may represent a good compromise between the needs of microbiologically controlled fermentation and a modern vision of wine as natural expression of its “terroir”, also from the microbiological point of view.