The complement system is a crucial part of the innate immune system that plays a key role in defending against pathogens and maintaining host homeostasis. It is activated by conformational changes in recognition molecular complexes upon sensing danger signals. The complement cascade is tightly regulated to ensure activation only at specific locations, avoiding host tissue damage. This review discusses recent advances in the molecular and structural basis of complement activation and regulation, focusing on the alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. It also discusses the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome (aHUS) and the development of complement inhibitors as therapies. The complement system is initiated by three distinct pathways – classical (CP), lectin (LP), and alternative (AP), each leading to a common terminal pathway. The AP is permanently active at low levels to monitor for pathogens. Healthy host cells are protected against complement attack and are resistant to persistent low-grade activation. The three pathways are activated on the surface of apoptotic cells, which are constantly generated within the body during normal cellular homeostasis. Complement activation during normal homeostasis and pathogen infection involves the central component C3. Activation of each of the three pathways results in cleavage of inactive C3 protein into the functional fragments C3a and C3b. C3a is an inflammation mediator and C3b is an opsonin, which can bind covalently and tag any surface in the immediate proximity to the site of its generation. The alternative pathway has a critical role in pathogen recognition and initiation of the complement cascade. However, the AP assures more than 80% of the terminal complement activity during pathogen recognition. Additional AP C3 convertases are formed on the C3b molecules generated either by CP activation or the AP C3 convertases. This chain reaction amplifies opsonization of the target and increases generation of anaphylatoxins. This amplification loop augments the effect of all pathways and is the heart of the complement cascade. The structural basis of complement activation and regulation involves recognition molecules such as C1q, MBL, and ficolins, which trigger each pathway only when and where it is necessary. The recognition event induces a structural change in the recognition molecule, which in turn induces the activation of enzymes able to cleave the subsequent molecules in the cascade and generate the central enzymatic complexes of complement, CP and AP C3 convertases. The mechanism of activation of the classical pathway involves the binding of C1q to its target surface, leading to a conformational change that transmits the signal from the gC1q domain via the CLR to induce auto-activation of C1r. This process is regulated by the C1 inhibitor, which binds and inactivates C1r andThe complement system is a crucial part of the innate immune system that plays a key role in defending against pathogens and maintaining host homeostasis. It is activated by conformational changes in recognition molecular complexes upon sensing danger signals. The complement cascade is tightly regulated to ensure activation only at specific locations, avoiding host tissue damage. This review discusses recent advances in the molecular and structural basis of complement activation and regulation, focusing on the alternative, classical, and lectin pathways, the formation of C3 and C5 convertases, the action of anaphylatoxins, and the membrane-attack-complex. It also discusses the importance of structure-function relationships using the example of atypical hemolytic uremic syndrome (aHUS) and the development of complement inhibitors as therapies. The complement system is initiated by three distinct pathways – classical (CP), lectin (LP), and alternative (AP), each leading to a common terminal pathway. The AP is permanently active at low levels to monitor for pathogens. Healthy host cells are protected against complement attack and are resistant to persistent low-grade activation. The three pathways are activated on the surface of apoptotic cells, which are constantly generated within the body during normal cellular homeostasis. Complement activation during normal homeostasis and pathogen infection involves the central component C3. Activation of each of the three pathways results in cleavage of inactive C3 protein into the functional fragments C3a and C3b. C3a is an inflammation mediator and C3b is an opsonin, which can bind covalently and tag any surface in the immediate proximity to the site of its generation. The alternative pathway has a critical role in pathogen recognition and initiation of the complement cascade. However, the AP assures more than 80% of the terminal complement activity during pathogen recognition. Additional AP C3 convertases are formed on the C3b molecules generated either by CP activation or the AP C3 convertases. This chain reaction amplifies opsonization of the target and increases generation of anaphylatoxins. This amplification loop augments the effect of all pathways and is the heart of the complement cascade. The structural basis of complement activation and regulation involves recognition molecules such as C1q, MBL, and ficolins, which trigger each pathway only when and where it is necessary. The recognition event induces a structural change in the recognition molecule, which in turn induces the activation of enzymes able to cleave the subsequent molecules in the cascade and generate the central enzymatic complexes of complement, CP and AP C3 convertases. The mechanism of activation of the classical pathway involves the binding of C1q to its target surface, leading to a conformational change that transmits the signal from the gC1q domain via the CLR to induce auto-activation of C1r. This process is regulated by the C1 inhibitor, which binds and inactivates C1r and