We present a method for fast reconstruction in fluorescence optical tomography with very large data sets. In recent reports, CCD cameras at multiple positions have been used to collect optical measurements, producing more than 10(7) data samples. This makes storage of the full system Jacobian infeasible, and so data are usually subsampled. The method reported here allows use of the full data set, via image compression methods, and explicit construction of the (small) Jacobian, meaning optimal inversion methods can be applied, and thus leading to very fast reconstruction.