Both orthographic regularity and visual familiarity have been implicated as contributors to the efficiency of processing visually presented words. Our studies sought to determine which of the internal codes representing words in the nervous system are facilitated by these two variables. To do this, sets of letter strings in which orthography and familiarity were factorially combined were used as the basis for physical, phonetic, semantic, and lexical judgments. The data indicated consistent effects of orthography on the activation of all codes. These effects were seen in same-different matching and in judgments of stimulus orientation, which are based on visual codes; in judgments of pronounceability based on phonetic codes; in judgments of meaningfulness based on semantic codes; and in lexical decisions, which are based on phonetic and semantic codes together. Familiarity, on the other hand, had a clear influence on the activation of semantic codes and to a lesser extent affected phonetic codes. Despite previous positive results found in matching letter strings, however, no influence of familiarity occurred in judgments based on visual codes once evidence for criterion shifting was eliminated. Our negative results included direct tests of facilitation in matching acronyms (e.g., FBI) and in matching both regular and irregular strings familiarized by specific training. It now appears that earlier findings of visual familiarity effects may be attributed to response biases resulting from the activation of higher level codes sensitive to familiarity, and to the use of small sets of training stimuli that allowed subjects to induce orthographic-like rules. The results obtained so far with our methods seem to reconcile an inconsistent literature by showing that speeded decisions based on visual codes are most strongly influenced by rule-governed processing mechanisms sensitive to orthographic structure, whereas decisions based on phonetic and semantic codes are affected about equally by rule-governed mechanisms and by stimulus-specific mechanisms sensitive to familiarity. This conclusion may lead to changes in notions of how effective various kinds of visual training are likely to be at different stages in the acquisition of reading skill.