Alex's research interests are in computational science and engineering (CSE), high performance computing, and bioinformatics. Within CSE, his research is in combinatorial scientific computing (CSC), an interdisciplinary research area where discrete mathematics and algorithms are applied to combinatorial problems from the sciences and engineering. CSC links scientific computing to algorithmic computer science.

Alex has contributed to several areas in CSE such as sparse matrix computations, graph partitioning, spectral graph algorithms, parallel computing, Automatic Differentiation, and computational systems biology. This work has applications to modeling chromatographic separations in chemical engineering; controlling electric power grids; modeling electronic circuits and devices; visualizing organs as they deform during surgery; identifying protein biomarkers for lung and prostate cancer; and understanding the proteomics of the human T-cell leukemia virus.

Alex has held earlier appointments in the computer science departments at Penn State, Waterloo, Wisconsin, Old Dominion, and ICASE, a research institute at NASA Langley Research Center.

Alex has mentored eleven PhD students, six post-doctoral scientists, more than sixty Master's students, and several undergraduate researchers. His advisees hold appointments at Penn State, Waterloo, Australian National University, and Drexel; Microsoft, IBM, Oracle, and Conviva Corporation; and Lawrence Livermore National Labs, Pacific Northwest National Lab, Argonne National Lab, etc. He has been honored as the most inspiring teacher by both undergraduates and graduate students. He has received the Director's Silver Medal and a Distinguished Alumnus Award from the Indian Institute of Technology in Delhi, the National Science Talent Scholarship, and an IBM University Research award.

Alex has led the effort to organize a CSC research community, chairing the first three international workshops in CSC, and serving as the Chair of the CSC steering committee. He serves as the editor of the Journal of the ACM (Scientific and High Performance Computing area), Society for Industrial and Applied Mathematics (SIAM) Books, SIAM Review, SIAM Monographs in CSE, and the International Journal of CSE. He has served as an editor of the SIAM Journal on Scientific Computing, and the Electronic Transactions on Numerical Analysis.

Alex Pothen served as the Director of the Combinatorial Scientific Computing and Petascale Simulations (CSCAPES) Institute, funded by the U.S. Department of Energy Office of Science for 2006-2012. The CSCAPES Institute involved thirty researchers from Purdue, Sandia National Labs, Argonne National Lab, Ohio State, and Colorado State. CSCAPES researchers focused on computational tools in combinatorial scientific computing that enable large-scale computational models in science and engineering on peta-scale computers. These tools included parallelization and load-balancing software, automatic differentiation technology, parallel graph and sparse matrix algorithms, and transformations to improve the memory system performance of sparse computations.