The dramatic drop in DNA sequencing costs has created many opportunities for novel biological research. These opportunities largely rest upon the ability to effectively compare newly obtained and previously known sequences. This is commonly done with BLAST, yet using BLAST directly on new datasets requires substantial technical skills or helpful colleagues. Furthermore, graphical interfaces for BLAST are challenging to install and largely mimic underlying computational processes rather than work patterns of researchers. We combined a user-centric design philosophy with sustainable software development approaches to create Sequenceserver (http://sequenceserver.com), a modern graphical user interface for BLAST. Sequenceserver substantially increases the efficiency of researchers working with sequence data. This is due first to innovations at three levels. First, our software can be installed and used on custom datasets extremely rapidly for personal and shared applications. Second, based on analysis of user input and simple algorithms, Sequenceserver reduces the amount of decisions the user must make, provides interactive visual feedback, and prevents common potential errors that would otherwise cause erroneous results. Finally, Sequenceserver provides multiple highly visual and text-based output options that mirror the requirements and work patterns of researchers. Together, these features greatly facilitate BLAST analysis and interpretation and thus substantially enhance researcher productivity.