Although approximately 50% of cancers give rise to metastases via the lymphatic system, the mechanisms mediating this process have remained unknown. In this study, we have investigated the role of two lymphatic endothelial molecules, the mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 in adhesion of malignant cells to the lymphatic endothelium, and analyzed their expression in two clinical series consisting of squamous cell cancers of the head and neck (n = 17) and breast cancers (n = 72). Affinity of the tested head and neck cancer cell lines to the lymphatic endothelium varied greatly, but adhesion of all cell lines was dependent on both the MR and CLEVER-1. Almost all cancer specimens contained peritumoral vessels that expressed CLEVER-1 and MR, and also the intratumoral lymph vessels often expressed them in both tumor types. However, only intratumoral expression of these molecules seems to be essential for metastatic spread to the regional lymph nodes. Only 8 (22%) of the 36 axillary node-negative breast carcinomas expressed the MR on the intratumoral lymph vessels as compared with 16 (50%) of the 32 node-positive carcinomas (P = 0.017), and all eight head and neck carcinoma patients with regional lymph node metastases at diagnosis had tumors that expressed CLEVER-1 on the intratumoral lymph vessels. These data suggest a role for both the MR and CLEVER-1 in directing the traffic of cancer cells within the lymphatic system.