Cryo-EM has recently undergone rapid progress in terms of achievable resolutions, driven by advances in detector hardware and image processing methods. Our group is focused on developing methods that make the technique more accessible and applicable and I will discuss two of the approaches which we are developing. The first seeks to overcome problems inherent in current cryo-EM specimen preparation methods, by combining cryo-EM with native mass spectrometry. After gently ionizing protein complexes, passing them through a mass spectrometer, and landing them onto EM grids we hope to build optimal cryo-EM samples one complex at a time. The second utilizes computational control of a high-end electron microscope to change the image defocus as movies are being recorded. Information from the individual frames with different defoci can then be combined leading to an image with enhanced contrast. I will present our current results with both techniques and discuss the remaining challenges and prospects.