Annexins are a family of membrane interacting proteins, widely distributed in vertebrates. Their involvement in the endosomal transport is due to annexin capability of binding cellular constituents such as membrane phospholipids and intracellular protein partners in a calcium dependent manner. Furthermore, annexins, through endosomal transport of particular receptors and specific cargo, may regulate various processes involved in signal transduction. Cell surface receptors after activation by signal molecule are internalized during endocytosis and transduce signal downstream the signaling pathway. The optimal conditions to modulate the signal are provided by the compartment specific membrane platforms carrying signal transducing complexes. In this review we describe a role of some members of the annexin family, annexin A1 (AnxA1), annexin A2 (AnxA2), annexin A6 (AnxA6) and annexin A8 (AnxA8) in the epidermal growth factor (EGF) signal transduction pathway. Annexins due to their specialized structure and specific localization in the cell may modulate signal transduction either directly, by interacting with EGF receptor (EGFR) or indirectly by interacting with EGF pathway regulators and effectors, by participating in formation and stabilization of the cholesterol enriched signal transduction platforms and by participating in EGFR transport and degradation.