Factor H (FH) is the major plasma regulator of the central complement protein C3b in the alternative pathway of complement activation. The elucidation of the FH interactions with five major ligands (below) is complicated by their weak μM dissociation constants K(D) and FH multivalency. We present the first survey of all the K(D) values for the major FH-ligand interactions and critically review their physiological significance. (i) FH self-association is presently well-established. We review multiple data sets that show that 5-14% of FH is self-associated in physiological conditions. FH self-association is significant for both laboratory investigations and physiological function.(ii) The FH-C3b complex shows low M affinity, meaning that the complex is not fully formed in plasma. In addition, C3, its hydrolysed form C3u, and its cleaved forms C3b and C3d show multimerisation. Current data favour a model when two C3b molecules bind independently to one FH molecule, as opposed to a1:1 stoichiometry where FH wraps itself around C3b.(iii) Heparin is often used as an analogue of the polyanionic host cell surface. The FH-heparin complex also shows a low M affinity, again meaning that complexes are not fully formed in vivo. The oligomeric FH-heparin complexes clarify a two-site interaction model of FH with host-cell surfaces.(iv) Reinvestigation of the FH and C-reactive protein (CRP) interaction revealed that this can only occur in plasma when CRP levels are elevated during acute-phase conditions. Given that CRP binds more weakly to the His402 allotype of FH than the Tyr402 allotype, this suggested a link with age-related macular degeneration (AMD).(v) FH activity is inhibited by zinc, which causes FH to aggregate strongly. High levels of bioavailable zinc occur in sub-retinal pigment epithelial deposits which lead to AMD. Excess zinc binds weakly to a central region of FH, explaining how zinc inhibits FH regulation of C3b.