The ability to generate massive amounts of sequencing data continues to overwhelm the processing capacity of existing algorithms and compute infrastructures. Calculating the similarities between a pair of genomic sequences is one of the most fundamental computational steps in genomic analysis. This step -called sequence alignment-is formulated as an approximate string matching (ASM) problem, which is typically solved using computationally expensive dynamic programming algorithms. In this work, we introduce SneakySnake, a highly parallel and highly accurate pre-alignment filter that remarkably reduces the need for the computationally costly sequence alignment step. The key idea of SneakySnake is to provide fast and highly accurate filtering by reducing the ASM problem to the single net routing (SNR) problem in VLSI chip layout. In the SNR problem, we are interested in only finding the path that connects two terminals with the least routing cost on a special grid layout that contains obstacles. The SneakySnake algorithm quickly and optimally solves the SNR problem and uses the found optimal path to decide whether performing sequence alignment is necessary. We also build two new hardware accelerator designs, Snake-on-Chip and Snake-on-GPU, that adopts modern FPGA (field-programmable gate array) and GPU (graphics processing unit) architectures, respectively, to further boost the performance of our algorithm.SneakySnake significantly improves the accuracy of pre-alignment filtering by up to four orders of magnitude compared to the state-of-the-art pre-alignment filters, Shouji, GateKeeper, and SHD. SneakySnake accelerates the state-of-the-art CPU-based sequence aligners, Edlib and Parasail, by up to 37.6× and 43.9×, respectively, without requiring hardware acceleration. The addition of Snake-on-Chip and Snake-on-GPU as a pre-alignment filter reduces the execution time of four state-of-the-art sequence aligners, designed for different computing platforms, by up to 689× (101× on average).To our knowledge, SneakySnake is the fastest and most accurate pre-alignment filtering mechanism that greatly enables the speeding up of genome sequence alignment while preserving its accuracy. It is the only pre-alignment filtering mechanism that is universal, as it works on all modern high-performance computing architectures, i.e., CPUs, GPUs, and FPGAs, by having software as well as software/hardware co-designed versions. Unlike most existing works that aim to accelerate sequence alignment, SneakySnake does not sacrifice any of the aligner capabilities (i.e., scoring and backtracking), as it does not modify or replace the aligner. The three versions of SneakySnake are open source and freely available online at https://github.com/CMU-SAFARI/SneakySnake/.