Today, matrix-based screens are used primarily for smaller and medium-size clone collections in combination with automation and cloning techniques that allow for reliable and fast interaction screening. Matrix-based yeast two-hybrid screens are an alternative to library-based screens. However, intermediary forms are possible too and we compare both strategies, including a detailed discussion of matrix-based screens. Recent improvement of matrix screens (also called array screens) uses various pooling strategies as well as novel vectors that increase their efficiency while decreasing false-negative rates and increasing reliability.