ADAM (a disintegrin and metalloproteinase) proteins are type-1 transmembrane and secreted proteins that function in cell adhesion and signal transduction. Here we review the structural features of ADAM proteins that direct their biological functions in ectodomain shedding and cell adhesion. Impact statement Recent structural advances have provided a deeper appreciation for interdomain relationships that modulate the activity of ADAM proteins in ectodomain shedding and cellular adhesion. Our review covers these new findings, and places them into historical context. The new results make clear that the metalloproteinase domain works in combination with its ancillary domains to execute its biological function. The ADAM ectodomain is dynamic, and accesses conformations that require interdomain movements during its enzymatic “lifecycle.” Fundamental questions about ADAM activation and substrate selection, however, still remain unanswered. Elucidating the biochemical and structural basis for ADAM regulation will be an exciting avenue of future research that should greatly advance our understanding of ADAM function in biology and human pathogenesis.