The activation of complement results in the opsonization of particles for removal by the reticuloendothelial system. Experimental evidence suggests that complement-mediated clearance of liposomal systems may significantly contribute to liposome biodistribution. Because of the multiplicity of complement activation mechanisms and the large number of proteins in the pathway, there are multiple opportunities to reduce or eliminate the opsonic effects of complement activation. This review addresses the state of our understanding of the interaction of liposomes with complement proteins and suggests some approaches to minimize complement activation.