The zinc finger antiviral protein (ZAP) selectively binds RNAs containing high numbers of CpG dinucleotides and mediates their degradation via its cofactors tripartite motif-containing protein 25 (TRIM25) and KH and NYN domain-containing protein (KHNYN). To evade this restriction, many RNA viruses, including human immunodeficiency virus 1 (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), show a marked suppression of CpG dinucleotides in their genomes, mimicking the dinucleotide composition of their vertebrate hosts. ZAP has been suggested to be one of the driving forces behind CpG suppression in viral genomes. However, it remained unclear whether the CpG suppression of viruses, such as HIV-1 and SARS-CoV-2 is sufficient to completely evade ZAP-mediated restriction. Furthermore, it remained unclear whether ZAP sensitivity of viral pathogens is simply determined by the frequency of CpGs or localization and structural environment also play a role. To answer these open questions, I analysed the level of restriction exerted by ZAP and the determinants of ZAP sensitivity in HIV-1 and other primate lentiviruses, as well as SARS-CoV-2. In addition, I wanted to obtain new insights into the role of ZAP and CpG suppression in cross-species transmissions and adaptation of these RNA viruses. My findings revealed that ZAP is expressed in primary target cells of HIV and coronaviruses. CpG dinucleotides are generally suppressed in the genomes of lentiviruses as well as coronaviruses albeit to different extents even among closely related strains. For example, CpG frequency is significantly higher in HIV-2 compared to its precursor SIVsmm infecting sooty mangabeys. In comparison, bat coronaviruses exhibit a broad range of CpG suppression, with the closest relatives of SARS-CoV 2 being the most CpG-depleted. Both primate lentiviruses and SARS CoV-2 are inhibited by endogenous ZAP expression, especially in the presence of IFN. Surprisingly, lentiviral susceptibility to ZAP does not correlate with the overall genomic CpG content. Instead, I identified a ~700 nucleotide region in the 5’ end of the env gene (termed ZAPsen) that predicted ZAP sensitivity of HIV-1 strains. Experimental introduction of additional CpGs in this region inhibited infectious virus production in the presence of ZAP. Altogether, my findings demonstrate that ZAP is a broadly acting component of the cell-intrinsic antiviral immune responses against diverse RNA viruses. It significantly contributes to the antiviral effects of IFNs. Furthermore, ZAP continues to exert evolutionary pressure on viral CpGs and restricts HIV-1 and SARS-CoV-2, despite the fact that these viruses and their animal precursors are adapted to the low CpG environment in humans.