It is long known that antiphospholipid antibodies (aPL) induce proinflammatory and procoagulant cellular responses. The underlying signal transduction has been a major focus of research and is the topic of this review. An amazingly heterogeneous panel of signaling pathways has been described and it turns out that at least some of this heterogeneity can be explained by effects of distinct aPL species. On the one hand, there are antibodies against β2-glycoprotein I (β2GPI) which appear to exert their cellular effects only as a complex of β2GPI/anti-β2GPI. Their major targets are low-density lipoprotein-receptor related protein 8 (LRP8), annexin A2 (ANXA2), toll-like receptor 4 (TLR4), and possibly TLR2. The other relevant aPL species are antibodies against cardiolipin which are internalized into endosomes and induce cellular responses via activation of endosomal NADPH-oxidase. Their cell surface target is still unknown. Another important issue relates to the role of complement. It has been shown in vivo that certain pathogenic effects of aPL depend on complement activation, but the exact interplay with the signaling pathways described earlier needs to be elucidated. Thus, while there has been tremendous progress over the past decade, many open questions remain to be answered.