Filaggrin and trichohyalin are the two major intermediate filament associated proteins which interact with keratin filaments in the skin. These two proteins initially accumulate in cytoplasmic granules called keratohyalin or trichohyalin granules which provide prominent morphological hallmarks of differentiation in the epidermis and the inner root sheath of hair follicles, respectively. The contents of each of these granules are modified and subsequently released into the cytoplasm of the fully mature cells where they function in the role of aggregating keratin filament bundles. We are beginning to identify several important aspects relative to the unique biological functions of both filaggrin and trichohyalin during the late stages of keratinocyte differentiation. This overview summarizes recent work on these proteins and will also highlight the existence of novel cytoplasmic granules, keratohyalin-trichohyalin hybrid granules, in dorsal tongue epithelia.