The nicotinamide adenine dinucleotide (NAD) biosynthetic enzyme nicotinamide phosphoribosyltransferase (NAMPT) has emerged as a promising new target for the treatment of multiple malignancies, including chronic lymphocytic leukemia (CLL). However, results of early phase clinical trials suggest that effective use of NAMPT inhibitors will require the dose reduction and improved treatment efficacy afforded by combination therapy. In this study, we assessed the downstream effects of NAMPT inhibition on NAD-dependent pathways in primary CLL cells in vitro in order to identify promising targets for novel combinations therapies. We then investigated drug-drug interactions between the NAMPT inhibitors FK866 and GMX-1778, and chemotherapeutics and targeted agents in current clinical use, as well as agents targeting mitochondrial metabolism, glycolysis and oxidative stress. We identified several promising novel drug combinations for further investigation and development for CLL treatment.