The detection of cervical carcinoma and its malignant precursors is currently accomplished using the Pap smear in conjunction with testing for the presence of human papillomavirus (HPV). This screening approach is successful at identifying patients with cervical disease with a very high sensitivity, but with limited specificity. In order to improve the accuracy of cervical disease detection and diagnosis, a number of approaches have been employed to incorporate molecular diagnostics into the testing procedure. Two investigational approaches to identify biomarkers have been employed: (1) the use of specific biomarkers based upon known keratinocyte response to HPV infection; and (2) the use of genome-wide expression profiles to identify new genes whose expression is altered in response to HPV infection and the transformation process. Both approaches have identified biomarkers that appear suitable for the detection of the mild dysplasia precursors of disease, the malignant precursors of moderate-severe dysplasia and cervical carcinoma. Some biomarkers are suitable for the detection of HPV infected cells displaying mild dysplasia while others are more specific to moderate-severe dysplasia and carcinoma (disease-specific markers). The disease-specific markers appear to be over-expressed in high-grade cervical disease and represent aberrant entry of the infected cells into the S-phase of the cell cycle. These markers appear promising in molecular diagnostic applications to detect malignant cells in both histology and cervical cytology specimens. An emerging diagnostic paradigm will be discussed where HPV DNA analysis represents measurements of transient infection and risk for future disease; analysis of HPV oncogene transcripts distinguishes active versus transient infection; and detection of aberrant S-phase induction represents a measure of active disease.