In this study, we investigated how activation unfolds in sign production by examining whether signs that are not produced have their representations activated by semantics (cascading of activation). Deaf signers were tested with a picture–picture interference task. Participants were presented with pairs of overlapping pictures and named the green picture (target) while ignoring the red picture (distractor). In Experiment 1 we varied whether target and distractor pictures had similar signs. Signs were produced faster with sign-related picture pairs compared to unrelated picture pairs. The facilitation observed with sign-related pairs replicates the 1 obtained in speaking with sound-related pairs (e.g., bed–bell), a finding cited in support of cascading of activation. In Experiments 2A and 2B we focused on sign iconicity, anticipating that cascading of activation would lead to a facilitatory effect of iconicity. Consistent with this prediction, picture distractors with iconic signs induced faster responses. Furthermore, in Experiment 3, facilitation was found for iconic signs in picture naming. Altogether, our results reveal that cascading of activation is a fundamental aspect of language processing that is at play not only in speaking, but also in signing. Our results also help to define which signs are activated in sign production.