This chapter presents the theoretical and methodological foundation that supports this research and introduces some of the challenges entailed in the translation of comics. It provides an overview of research on the translation of comics, highlighting how several studies have disregarded the multimodal nature of this medium. In this respect, the general contribution of multimodal studies to translation is discussed, by tackling concepts such as transduction (Kress 2003; Kress 2010) and resemiotisation (Iedema 2003). It is argued that the multimodal approach can be successfully applied to the study of comics (Dunst et al. 2018; Asimakoulas, 2019) and comics in translation (Kaidl 2000, 2004; Borodo 2014, 2023a). The notion of ‘isotopy’ is foregrounded in the analysis, as a potential tool guiding the interpretation and translation of comics. Isotopy refers to the iterative nature of units of signification—both verbal and visual—which provides semantic cohesion and consistency of a discourse. The notion was first introduced in semiotics by Greimas (1995[1966], 2012[1970]) and further explored as an interpretative category by semioticians such as Eco (1979), Rastier (2009[1987]), Fontanille (2003), Bertrand (2000), and Binelli (2013a). Though research on isotopies traditionally focused on literary texts (e.g., Mudersbach and Gerzymisch-Arbogast 1989; Nord 2005; Binelli 2013b), it is argued that its study may be extended to multimodal texts such as comics (Groensteen 2007), in which non-verbal items participate in meaning-making processes, and thus to the creation of isotopies. The translation of comics may benefit from the application of a tool to study the relations of signification of both verbal and graphic devices without assigning an a priori privileged position to either of them. Subsequently, this chapter illustrates how this methodological framework can tackle the challenges that the translation of comics entails. For example, translators often tend to look only at the verbal dimension of comics, thus disregarding the meaning-making processes of the word-image interplay. In addition to the issues related to the multimodal nature of comics, potential problems connected to the translation of culturemes, the differences in comics traditions, audience expectations, and frames of interpretation is investigated.