One of the most important families of chemicals used in minerals processing is depressants. Most often, the flotation separation of individuals minerals from complex massive ores is not possible without the use of these reagents. In practice, when treating complex sulphide ores, the use of two or more depressants is common, especially when a selectivity problem is present or separation of several valuable minerals is required. The use of two or more depressants is referred to as a depressant system. Research and development work has been carried out to develop and define depressant systems for beneficiation of massive sulphide lead-zinc, copper-zinc and copper-lead-zinc ores. Three major groups of depressants have been studied in various combinations. There are: inorganic depressants, organic depressants, and depressants with multifunctional roles (i.e. modifier-depressants). Of particular interest is a new class of depressants derived from organic chemicals. Marked differences in performance of depressant systems (i.e. combinations of two depressants) as compared to the performance of an individual depressant have been observed with a number of organic and inorganic depressant combinations. This was mainly attributed to the conditions and environment changes created by the use of the two depressants. In some cases, the performance of one depressant was greatly improved in the presence of another. The performance of the depressant system was not a function of type of collector used but the order of addition was important. The performance of different depressant systems was investigated using laboratory-scale batch tests, optical microscopy and continuous flotation tests.