The study of sign language has received increasing interest in the last decades. Within this growing field, research on sign language processing – including both comprehension and production – has also received a remarkable boost in recent years. At initial stages of research, efforts were concentrated on demonstrating universal aspects of language processing; thus, little attention was paid to the differences between modalities or to the specific aspects of the sign-modality. However, the wide recognition of sign languages as natural languages has supported a greater interest in furthering our understanding of modality specific factors (e.g., the use of proprioceptive and spatial information for phonological encoding or the greater potential for iconicity). This chapter offers a comprehensive overview of the most relevant studies of sign language comprehension and production that focus on the lexical level of processing. Results from behavioural studies, as well as evidence of similar neural substrates underlying speech and sign processing, have led to the widely accepted assumption that universal language processing principles can explain lexical access in both signed and spoken languages. However, although psycholinguistic and cognitive mechanisms as well as neural networks underlying speech and sign processing are strikingly similar, they are not identical. We propose that the study of the differences in processing of speech and signs can lead to a more complete picture of human language processing. Acknowledging these differences can also point researchers to factors influencing spoken language processing that might have been under-researched so far.