The ordinary Fourier transform is suited best for analysis and processing of time-invariant signals and systems. When we are dealing with time-varying signals and systems, filtering in fractional Fourier domains might allow us to estimate signals with smaller minimum-mean-square error (MSE). We derive the optimal fractional Fourier domain filter that minimizes the MSE for given non-stationary signal and noise statistics, and time-varying distortion kernel. We present an example for which the MSE is reduced by a factor of 50 as a result of filtering in the fractional Fourier domain, as compared to filtering in the conventional Fourier or time domains. We also discuss how the fractional Fourier transformation can be computed in O(N log N) time, so that the improvement in performance is achieved with little or no increase in computational complexity.