In this review, we first consider the inherent structural constraints for binding of a peptide to MHC class II molecules. Such parameters at the site of TCR recognition are dependent upon the efficient generation of the antigenic determinant during natural processing of the whole protein antigen. Strikingly, only a minor fraction of such potential determinants on an antigen are presented in an immunodominant manner, while the remaining peptides are silent (cryptic). Why one determinant is selected while the majority are neglected is still unresolved, but we review the experimental evidence pertaining to this choice. Thus, features of the antigen remote from the actual determinant can either steer processing toward disclosure or revelation of a determinant, or interfere with the binding of peptides to MHC (hinderotopy). The evidence is reviewed for "MHC-guided processing," where the unfolding antigen binds at an early stage to an MHC molecule through its most available and affine agretope and then is trimmed down to final size, while the rest of the molecule, including cryptic determinants, is discarded. Different MHC molecules can compete for determinants at an early stage of processing when the antigen is close to its original length. There are shifts in the hierarchy of display of dominant and cryptic determinants, and these shifts relate to local inflammatory states, to changes in the state or composition of the APC population, and to aspects of exogenous vs endogenous processing. The impact of this differential display of determinants on tolerance and autoimmunity is discussed.