Abstract: Interfaces between organic semiconductors and two-dimensional (2D) materials have the potential to combine the useful properties of their constituents materials as well as host emergent physical phenomena. Despite this potential, there has been little systematic exploration of how the orbitals of a molecule and the bands of a 2D material interact to influence the properties of the combined system. Using the phthalocyanine/MoS2 heterojunction as a prototypical system, the effects of systematically changing the molecule’s electronic structure are explored in relation to the photonic and electrical response of the combined molecule/2D system. The non-frontier orbitals of the phthalocyanine are found to play a key role in coupling to the MoS2, as illustrated by Raman, photoluminescence, and electrical measurements. These results show the importance of considerations beyond a simple band alignment picture of organic/2D interfaces and inform the design of next-generation optoelectronic devices.