Background: Tumor heterogeneity and clonal selection contribute to resistance to molecular targeted therapies. Dynamic tracking of urine cfDNA mutations can offer a noninvasive tool for monitoring therapeutic efficacy. Methods: cfDNA was isolated from single or sequential urine samples from patients with advanced cancers and archival tumor tissue with BRAF V600E from a CLIA-certified laboratory. Assays for quantitative detection of BRAF V600E and KRAS G12/13 mutations in urine cfDNA were developed using digital droplet (dd) PCR and next generation sequencing. Analytical sensitivity of BRAF V600E and KRASG12/13 assays is 0.03% and 0.006% mutant alleles in wild-type DNA background. Results: Urine cfDNA was examined in 34 patients (melanoma, n = 11; colorectal cancer, n = 8; papillary thyroid carcinoma, n = 5; non-small cell lung cancer, n = 5; other, n = 5) with BRAF V600E in tumor tissue. 32 of 34 patients (94%) had the same mutation in urine cfDNA (mutant, n = 22; low-mutant, n = 10). Longitudinal analysis in 25 (74%) patients (treated with: BRAFi, n = 23; MEKi, n = 1; none, n = 1) showed that changes in BRAF V600E cfDNA amounts correlated with percent changes in target lesions on imaging (r = 0.68, p < 0.001). Patients with decreased BRAF V600E cfDNA (n = 16) compared to others (n = 8) had a trend to a longer median time-to-treatment failure (8.8 months, 95% CI 8.1-9.5 vs. 2.2 months, 95% CI 0.0-5.1; p = 0.07) on BRAF or MEK therapy. Moreover, 22 (65%) patients had a low frequency KRAS G12/13 mutation (median 3.4 copies/10⁵ genome equivalents) in urine cfDNA that was previously undetected in tumor by CLIA, except in one case. 9 of 9 patients with urine examined at the time of progression had detectable cfDNA KRAS G12/13. Re-analysis of the retrieved archival tumor tissues from 8 patients found a previously undetected low frequency (1.3%) KRASmutation in one sample by ddPCR. Conclusions: Our results suggest that 65% of patients with advanced cancers and BRAF mutation in tumor tissue have low frequency KRAS G12/13 mutations in urine cfDNA undetected in tumor samples by standard CLIA technologies. Low frequency KRAS mutations can plausibly drive resistance to BRAF targeting agents, and these may be detected in urine cfDNA.