Porphycenes have been shown to exhibit many advantageous properties when it comes to the application of two-photon absorption (TPA), a technique with potential use in the area of photodynamic therapy (PDT). A computational study of structure-reactivity relationships in the one- and two-photon absorption spectra of a series of 2,7,12,17-substituted porphycenes has been carried out using linear and quadratic density functional response theory. The focus has been on determining the effect on the spectra of electron donating and withdrawing substituents, the outcome of extending the conjugation lengths to these substituents, and the consequence of formation of metallo-porphycene complexes. In particular, we have looked at the use of TPA in order to improve the penetration depth of the therapeutic light dose, in terms of the position of the absorption maximum with respect to the optical window of tissue penetration, as well as the effect on the TPA cross section. The extent of conjugation was shown to be particularly crucial for increasing the TPA cross section, for both the electron withdrawing and donating substituents, while the inclusion of a metal in the center of the macrocycle was shown to benefit the absorption wavelength in terms of tissue penetration considerations.