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Simple Summary: Small cell lung cancer (SCLC) is an aggressive tumor, which can occur either de novo or from the histologic transformation of non-small cell lung cancer. Liquid biopsy has demonstrated its capability to detect, characterize and monitor different cancers. The aim of this systematic review was to assess the potential added value of liquid biopsy, in terms of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), in the management of SCLC, either de novo or transformed. We found ctDNA analysis as the most valuable and feasible technology to be integrated into clinical for disease monitoring (response, relapse, transformation) or for genomic profiling of SCLC, with a potential use also for prognostic stratification. CTCs hold a strong prognostic significance, as confirmed by our meta-analysis (even if potentially biased), but the heterogeneity of available data, the lack of agreed cut-offs, and the less affordable technology make CTCs more difficult to be integrated into present clinical practice. Background: The potential added value of liquid biopsy (LB) is not well determined in the case of small cell lung cancer (SCLC), an aggressive tumor that can occur either de novo or from the histologic transformation of non-small cell lung cancer (NSCLC). Methods: A systematic review of studies adopting LB in patients with SCLC have been performed to assess the clinical utility of circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs). Results: After a screening of 728 records, 62 studies (32 evaluating CTCs, 27 ctDNA, and 3 both) met predetermined eligibility criteria. Only four studies evaluated LB in the diagnostic setting for SCLC, while its prognostic significance was evaluated in 38 studies and prominently supported by both ctDNA and CTCs. A meta-analysis of 11 studies as for CTCs enumeration showed an HR for overall survival of 2.63 (1.71–4.05), with a potential publication bias. The feasibility of tumor genomic profiling and the predictive role of LB in terms of response/resistance to chemotherapy was assessed in 11 and 24 studies, respectively, with greater consistency for those regarding ctDNA. Intriguingly, several case reports suggest that LB can indirectly capture the transition to SCLC in NSCLC treated with EGFR tyrosine kinase inhibitors. Conclusions: While dedicated trials are needed, LB holds potential clinical roles in both de novo and transformed SCLC. CtDNA analysis appears the most valuable and practicable tool for both disease monitoring and genomic profiling. [ABSTRACT FROM AUTHOR]