The inability to propagate molluscum contagiosum virus (MOCV), which causes benign skin lesions in young children and more extensive infections in immunosuppressed adults, has constrained our understanding of the biology of this human-specific virus. In the present study, we characterized the RNAs synthesized in abortively infected cultured cells and a human skin lesion by high-throughput sequencing. These studies provided an initial transcription map of the MOCV genome, suggested temporal regulation of gene expression, and indicated that the in vitro replication block occurs prior to intermediate and late gene expression. RNAseq and reporter gene analyses, as described here, may help to evaluate and optimize conditions that enhance MOCV infection in vitro.