Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here, we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq), and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and autoregulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells. Display omitted ► Thousands of binding sites and splicing events identified for major hnRNP proteins ► HnRNP proteins act cooperatively, regulating cassette exons in similar directions ► HnRNP proteins cross- and autoregulate ► HnRNP proteins regulate other RNA binding proteins and cancer related genes Heterogeneous nuclear ribonucleoparticle (hnRNP) proteins are among the most abundant RNA binding proteins (RBPs) and regulate cellular RNA levels. Through the integration of several genomic approaches, Huelga, Yeo, and colleagues have identified thousands of binding sites, splicing events, and regulated genes for major hnRNP proteins A1, A2/B1, F, H1, M, and U. HnRNP proteins cross- and autoregulate each other and a whole network of RBPs. These findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins.