Combinatorial biological screens, such as those that assay genetic interactions between mutations or gene deletions, or that assay physical interactions between proteins, have historically been limited in throughput by the requirement to test for interactions one-at-a-time. A potentially higher-throughput alternative would be to provide each combination with a unique barcode and measure the interaction score of each barcoded genotype en masse in cell pools via barcode sequencing (bar-seq). However, construction and storage of a uniquely barcoded strain for each combination is impractical for genome-scale interaction screens. Here, we introduce a pair of novel double barcoding systems that allow us to easily construct and assay extremely large combinatorial libraries. The key innovation is a tandem “landing pad” in the yeast genome that allows two barcoded plasmid libraries to be brought to the same genetic location. Pooled growth of double barcode libraries and paired-end amplicon sequencing can be used infer the relative fitness of each pairwise interaction in a population. We show that this system can easily scale up to yeast pools containing 107 or 109 double barcodes, depending on whether barcode pairs are brought together by sequential integration or mating. As a proof-of-principle, we generated a library of ~3000 double barcoded haploid and diploid yeast strains, each with a different pair of auxotrophic rescue plasmids. We are currently assaying these pools across several environments to determine the fitness error rates of the assay. Additionally, we are porting our tandem integration platform to mammalian cell systems. This platform will be useful for a variety of applications including assays of interactome dynamics, as well as mammalian protein-protein interaction and CRISPR/Cas9-based genetic interaction assays.