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There's some good answers here, but another option I haven't seen suggested: Convert your txt file to HDF5 (Regardless if you follow my approach here, you should really consider converting your data to anything but a txt file). There's a nice library for working with it in python called h5py. The HDF format is designed specifically with working with very large sets of data (it even has compression options), often scientific in nature, but it's not a database. As far as how this fixes the specific issue you you've described, you can utilize numpy slicing to load one chunk your data at a time. Here's a stackoverflow answer which discusses a solution.