In high energy collisions involving small nuclei (p+p or x+Au collisions where x=p, d, or 3 He) the fluctuating size, shape and internal gluonic structure of the nucleon is shown to have a strong effect on the initial size and shape of the fireball of new matter created in the collision. A systematic study of the eccentricity coefficients describing this initial fireball state for several semi-realistic models of nucleon substructure and for several practically relevant collision systems involving small nuclei is presented. The key importance of multiplicity fluctuations in such systems is pointed out. Our results show large differences from expectations based on conventional Glauber model simulations of the initial state created in such collisions.