Leather industry is making significant contributions to economic development. However, it is notably leading to a serious environmental pollution. Recently, the enzyme technology developments offer new opportunities for enzymatic application in leather making. In the present investigation, microbial lipases were studied and used in degreasing process of sheep leathers. In order to optimize degreasing efficiency, a fractional experimental design with four parameters (enzyme source, processing stage, lipase amount, and degreasing duration) was used. Lipases A from Aspergillus niger , F from Rhizopus oryzae , R from Penicillium roqueforti , and AY from Candida rugosa were selected for leather degreasing. Enzymatic treatment of sheep skin was carried out during two stages of beamhouse operations: deliming-bating and pickling. Obtained results showed that enzymatic degreasing efficiency is higher than those obtained with the conventional process. Lipase F from Rhizopus oryzae demonstrated the most interesting hydrolysis with yields of 58.3% and 37.2% for delimed and pickled skins, respectively. An enzymatic degreasing process on pickled leather using 0.125% (w/v) of lipase F during 3.5 h is the most promising for an industrial application with a 76.03 of degreasing efficiency. Results of the physico-mechanical tests of leathers having undergone enzymatic treatment complied with industry requirement. The enzymatic treatment may be carried out in the same conditions as employed in leather manufacturing process. Results suggested that the enzymatic degreasing improves the leather quality and reduces the use of chemical compounds and surfactant.