The emergence of COVID-19 marks the greatest pandemic since the 1918 influenza. The virus has displayed a remarkable ability to mutate and increase its transmissibility from person to person. Changes in key amino acid sequences in coding regions of the SARS-CoV-2 genome has given rise to variants with diverse virulent properties. Is it possible to connect small scale sequencing changes to large scale evolutionary lineages? Spike, a glycoprotein that studs the surface of viral protein coats offers insight to this question. Spike acts as a key, attaching to the human ACE2 receptor. Once inside the human cell, the virus uncoats and hijacks cellular machinery to translate its proteins for later release. Genetic mapping reveals four patterns of spike mutation that enhance transmissibility and immune system evasion. Mutational patterns can stabilize or destabilize spike morphology, enhancing the process of virus-cell attachment and entry. Positively charged amino acid mutations located near the spike receptor binding domain enable specific variants to favorably interact with receptors on human cells. A deeper understanding of spike protein mutation is relevant to therapeutic developments that target emerging variants. Rapidly accumulating genetic mutations in the spike protein have given the virus the ability to persist within a short window of evolutionary time.