An efficient clearance and degradation system may be needed during microbial invasion which otherwise would lead to severe inflammation and eventually death. Non-specific defence mechanisms in fish play an important role at all stages in infection. The non-specific humoral defence including proteases, lysins and agglutinins, for example, in mucosal secretion is the first line of defence, whereas mucosal lining cells function as the second barrier against invasion. Blood cells, especially granulocytes and monocytes, may destroy microbes present in the circulation and may function as the third line of defence. Finally, endocytically active cells such as endothelial cells, macrophages and granulocytes in organs and tissues may take up and degrade microbes or microbial products. The endocytic and degradation processes strongly depend on the effectiveness of the reticuloendothelial system which consists of endothelial cells and macrophages that line small blood vessels (e.g. sinusoids and ellipsoids). Potentiation of non-specific defence mechanisms may occur during microbial invasion, leading to more efficient clearance and destruction of pathogens or other harmful substances. In microbial invasion, an inflammatory response such as elevated production of antimicrobial substances is often encountered. Central cells in the production of antimicrobial substances are macrophages and granulocytes, and microbial products in inflammation may alter the cells function to a more activated state in vivo. Activated cells may enhance their antimicrobial capacity and efficiency by producing higher amounts and more active antimicrobial agents. This review concerns the non-specific defence system and gives an introduction to some of the known non-specific humoral substances and their induction/suppression, and provides a more extensive introduction to cytokine research and immunomodulation. Cellular aspects of non-specific defence, including macrophages and their products, are discussed in the light of their function in the reticuloendothelial system in fish.