Progression of retinal degeneration in a mouse model was studied in vivo with high-resolution spectral-domain optical coherence tomography (SD-OCT). Imaging in 3D with high depth resolution (<3 μm), SD-OCT resolved all the major layers of the retina of control C57BL/6J mice. Images of transgenic mice having a null mutation of the rhodopsin gene revealed the anatomical consequences of retinal degeneration: thinning of the outer retina, including the outer plexiform layer (OPL), outer nuclear layer (ONL), and inner and outer segments (IS/OS). We monitored the progression of retinal degeneration in rd1 mice (C3H/HeJ) by periodically imaging the same mice from the time the pups opened their eyes on P13 to P34. SD-OCT images showed that the outer retina (OPL, ONL, IS/OS) had already thinned by 73% (100 to 27 μm) at eye opening. The retina continued to degenerate, and by P20 the outer retina was not resolvable. The thickness of entire retina decreased from 228 μm (control) to 152 μm on P13 and to 98 μm by P34, a 57% reduction with the complete loss in the outer retina. In summary, we show that SD-OCT can monitor the progression of retinal degeneration in transgenic mice.