The concept that macrofibril templates, the fibrillar precursor to complete macrofibrils incorporating matrix proteins in trichokeratins, are formed by intracellular anisotropic phase separation of intermediate filaments (IFs), is here developed in detail. The factors affecting structural development, including IF length dispersion, and presence of other macromolecular solutes, are discussed in terms of the statistical thermodynamic models presented over 30 years ago by P.J. Flory and co-workers. The crucial role of pendant IF head groups in controlling IF separation and stabilizing the mesophase is emphasised. In particular, a concerted process of polymerization of unit-length IF precursors coupled with continuous transfer of longer IFs to the anisotropic phase is invoked. Observed structures in differentiated cell lines in mature fibres are rationalised in terms of different possible nematic or double-twist liquid crystalline precursor structures, with varying degrees of anisotropic phase coalescence. The occurrence of rarely observed macromolecular double-twist structures is made plausible by qualitative analysis of mesophase mechanics and reference to alternative structures in other macromolecular mesogens. The model is consistent with, and explains, certain well-known features of mature fibre structure, such as filament-matrix ratios in different cell lines. A few comments relating to the infill of the template by keratin intermediate filament associated proteins (IFAPs) are presented. (C) 2010 Elsevier Inc. All rights reserved.