Responding to stimuli with certain features leads to a coupling of stimulus features and responses into so-called event files. If any component of this event file repeats, previous information is retrieved, affecting performance: In case of partial repetitions, responding is impaired. The resulting stimulus-response (S-R) binding effects can be modulated by top-down or bottom-up factors. In the current study, we were interested in how S-R binding effects are affected by familiarity and meaningfulness of stimuli. Participants discriminated the color of familiar and meaningful words and unfamiliar and meaningless non-words (Experiment 1) and familiar and meaningful letters and unfamiliar and meaningless mirrored letters (Experiment 2). S-R binding effects were larger for familiar and meaningful stimuli. In Experiment 3, we used names of musical instruments as stimuli with constant meaningfulness that only varied in their familiarity due to their frequency in the German language. Here, mere familiarity did not modulate S-R binding effects. Lastly, in Experiment 4, we asked participants to learn names and characteristics of bacteria images created by us – while equally often presenting bacteria images without name or characteristic; this should result in stimuli with equal familiarity but different degree of meaningfulness. In fact, stimuli with previously associated meaning again led to larger S-R binding effects. These results suggest that effects of binding and retrieval can be boosted by features that exceed pure perceptual components – specifically, meaningfulness of stimuli.