Fermentation of lignocellulosic hydrolyzates and other carbon sources to ethanol is affected by different substances present in the cultivation media. High concentration of sugars is desirable in all ethanol processes, in order to have a higher concentration of ethanol, thus reducing the cost of distillation. However, high concentrations of both sugars and ethanol inhibit the fermentation process. Furthermore, high concentration of various salts available in most of the industrial substrates such as sugarcane juice and molasses can also make a high osmotic stress for the fermenting microorganisms. These salts and some other impurities can be further accumulated with water saving programs, in which the stillages are recycled in order to reduce water consumption and wastewater production. The choice of pretreatment and/or hydrolysis of lignocellulosic materials can lead to a number of severe inhibiting compounds, including furans, carboxylic acids, and phenolic compounds. The inhibition effects of all these components can be reduced or removed by choosing a suitable concentration of the substrates and choosing a proper method for the pretreatment and/or hydrolysis steps in order to reduce the inhibitors. If the toxic compounds follow the culture, detoxification could be an option, although it has some expenses and might lead to partial loss of the sugars. However, choosing a right strategy for the fermentation by e.g. fed-batch process or continuous mode with high-cell density or encapsulated cells as well as a tolerant organism or an organism that can convert the inhibitors might avoid the necessity of the prior detoxification.