Early cancer detection is key to better patient outcomes. Conventional diagnostic examinations are invasive and only give a snapshot of disease. Liquid biopsy, promising though it is, is hampered by problems of circulating tumor DNA (ctDNA) in the earliest stages of cancer by low sensitivity and abundance. This review covers new liquid biopsy biomarkers other than ctDNA, their biological rationale, sophisticated means of detection, and clinical utility in early cancer diagnosis on the basis of only original research and case reports. We discuss Circulating Tumor Cells (CTCs), Extracellular Vesicles (EVs) including exosomes and their varied cargo (proteins, microRNAs, long non-coding RNAs, exosomal DNA), cell-free RNA circulating in the blood (cfRNA), circulating proteins, and circulating metabolites. Each provides distinct tumor biology information, complementing ctDNA. Their potential is hampered by problems of low concentration of tumor-derived material, biological heterogeneity, and the strong need for standardized isolation and detection procedures. Future progress will rely on multi-omics integration and artificial intelligence to improve diagnostic accuracy, with the aim of translating these technologies into everyday clinical practice for population and personalized cancer screening.