Purpose: Two types of orthographic knowledge were examined: i) knowledge of permissible letter combinations (general orthographic knowledge) and ii) knowledge of whole words (word-specific orthographic knowledge), to gain further insights into the relationship of general and word-specific orthographic knowledge with literacy skills. Method: Mediation models were estimated using a sample of 2,636 3rd and 4th grade children (50.6% female, ethnic backgrounds were not surveyed) to examine whether general orthographic knowledge predicts reading fluency and spelling performance and whether this path is mediated by word-specific orthographic knowledge. Using confirmatory factor analyses (CFA), we examined whether the responses to correctly spelled words/legal letter patterns and pseudohomophones/illegal letter patterns in word-specific and general orthographic knowledge tasks were generated by separate latent constructs. Results: Our results confirm that word-specific orthographic knowledge is a facilitatory mediator in the relationship between general orthographic knowledge and literacy skills. The relationship of general and word-specific orthographic knowledge with literacy skills varies by item type, with a tendency toward higher correlations between literacy skills with pseudohomophones (vs words) and illegal (vs legal) pseudowords, which is in line with the two-factor solution of the CFA. Conclusion: From a theoretical perspective, we conclude that general orthographic knowledge facilitates orthographic learning of words. From a methodological perspective, we encourage future researchers to distinguish between targets and foils in orthographic decision tasks.