The discovery of new fluorescent proteins (FPs) that emit in the far-red part of the spectrum, where light absorption from tissue is significantly lower than in the visible, offers the possibility for noninvasive biological interrogation at the entire organ or small animal level in vivo. The performance of FPs in deep-tissue imaging depends not only on their optical characteristics, but also on the wavelength-dependent tissue absorption and the depth of the fluorescence activity. In order to determine the optimal choice of FP and illumination wavelength we compared the performance of five of the most promising FPs, i.e. tdTomato, mCherry, mRaspberry, mPlum, and Katushka. We experimentally measured the signal strength through mice and employed theoretical predictions to obtain an understanding on the performance of different illumination scenarios, especially as it pertains to tomographic imaging. It was found that the appropriate combination of red-shifted proteins and illumination wavelengths can improve detection sensitivity in small animals by at least 2 orders of magnitude compared to Green FP (GFP). It is also shown that the steep attenuation change of the hemoglobin spectrum around the 600nm range may significantly affect the detection sensitivity and necessitates the careful selection of illumination wavelengths for optimal imaging performance.