In this issue of JAMA, Zhang and colleagues 1 report the emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant in Southern California that accounted for 44% (37 of 85) of samples collected and studied in January 2021. The terminology of viral variation can be confusing because the media and even scientific communications often use the terms variant, strain, and lineage interchangeably. The terminology reflects the basic replication biology of RNA viruses that results in the introduction of mutations throughout the viral genome. When specific mutations, or sets of mutations, are selected through numerous rounds of viral replication, a new variant can emerge. If the sequence variation produces a virus with distinctly different phenotypic characteristics, the variant is co-termed a strain. When through genetic sequencing and phylogenetic analysis a new variant is detected as a distinct branch on a phylogenetic tree, a new lineage is born. New variants become predominant through a process of evolutionary selection that is not well understood. Once identified, several questions arise regarding the potential clinical consequences of a new variant: Is it more readily transmitted; is it more virulent or pathogenic; and can it evade immunity induced by vaccination or prior infection? For these reasons, new viral variants are studied, leading to the terms variant under investigation or variant of concern. To communicate effectively about new SARS-CoV-2 variants, a common nomenclature is needed, which like the virus, is evolving. Fortunately, the World Health Organization (WHO) is working on a systematic nomenclature that does not require a geographic reference, since viral variants can spread rapidly and globally. Currently, the terminology is overlapping, as reflected in the report by Zhang et al. 1 This new variant (CAL.20C) is termed lineage 20C/S:452R in Nextstrain nomenclature, 2 referring to the parent clade 20C and spike alteration 452R. Similarly, using a distinct PANGO nomenclature, 3 this variant derives from lineage B (B.1.429 and B.1.427). While alterations in any viral genes can have implications for pathogenesis, those arising in the spike protein that mediates viral entry into host cells and is a key target of vaccines and monoclonal antibodies are of particular interest. The new variant, identified in California and termed 20C/S:452R, has 3 amino acid changes in the spike protein, represented using the single-letter amino acid nomenclature: S13I, W152C, and L452R. To interpret this new set of alterations, it is useful to review what is known about recent variants that have become predominant in other regions of the world.