Genetic screening has been a cornerstone in efforts to dissect the program that controls how cells exert their functions or break down in disease. High-throughput chemical screens typically employ coarse assays, (e.g. cell survival) or inspect gross anatomic phenotypes, limiting what can be learned about mechanisms of action, off-target effects, and heterogeneous responses. Single-cell sequencing provides a means of interrogating the molecular consequences of genetic, chemical, or environmental perturbations, but limited sample multiplexing in commercial platforms makes screening infeasible. We have developed and continue to improve various methods for highly multiplexed single-cell sequencing experiments. We have applied these tools to study diverse biological systems including cancer cells and whole zebrafish embryos.