Argonaute proteins are central to small RNA-guided gene silencing and have long been known to associate with a variety of protein cofactors across pathways and organisms. However, only a limited number of these interactions have been directly validated, and high-resolution structural insights into how Argonautes engage with their protein partners–and how such interactions influence function–remain limited. In this talk, we will present our recent cryo-EM findings revealing two previously unrecognized modes of Argonaute-protein interaction, shedding light on how these contacts may modulate Argonaute conformation and activity.