Top-down and bottom-up mass spectrometry methods can generate gas phase fragments and use these to identify proteins. Top down methods, in addition, can provide the mass of the protein itself and therefore additional structural information. Despite top-down’s conceptual advantage, the market share advantage belongs to bottom-up methods as a result of their more robust sample preparation, fragmentation, and data processing methods. Here we report improved fragmentation and data processing methods for top-down mass spectrometry. Specifically, we report the use of funnel-skimmer dissociation, a variation of nozzle-skimmer dissociation, and compare its performance to electron capture dissociation. We also debut BIG Mascot, an extended version of Mascot with incorporated top-down MS2 search ability, and the first search engine that can perform both bottom-up and top-down searches. Using BIG Mascot, we demonstrate the ability to identify proteins: 1) using only intact protein MS1, 2) using only MS2, and 3) using the combination of MS1 and MS2. We correctly identify proteins with a wide range of masses, including thirteen amyotrophic lateral sclerosis-associated variants of the protein Cu/Zn superoxide dismutase, and extend the upper mass limit of top-down protein identification to 669 kDa by identifying thyroglobulin.