Bioincompatibility reactions related to the non-physiology of the procedure have plagued dialysis from its early days. Although the problem is certainly multifactorial, the present overview selectively focuses on some aspects of activation of late complement (C) components, the importance of which may have been underappreciated in the past. Dialysis patients are poised for intense C activation because of cumulation of the low molecular weight factor D, an intrinsically active serine esterase which is not inhibited by any known endogenous inhibitor and catalyzes an early step in the alternative pathway. C activation reflects the net balance between activation and inhibition, the latter particularly via factor H binding. Dialyzer membrane characteristics that are related to factor H binding and regulation of initial activation steps include not only membrane surface chemistry but also its microdomain structure. Kinetic studies of the generation of the terminal complement complex (TCC) suggest ongoing generation throughout the duration of a dialysis session (in contrast to the transient release of C-derived anaphylatoxins). Potential consequences of TCC generation include amplification of the non-C-dependent cell activation signals through L-fucose-dependent steps. Efforts to reduce TCC generation by membrane engineering, for example, end group derivatization and optimization of microdomain structure, open perspectives for the development of more biocompatible membranes.