Tumor angiogenesis is important for the progression of cancer and is orchestrated by various factors associated with tumor vessels, tumor cells, and stromal cells. Angiogenic signaling in non-small cell lung cancer (NSCLC) needs to be further clarified, especially regarding existing and upcoming therapeutic approaches. Expression of CD34, CD105, Mel-CAM, VE-cadherin, D2-40, VEGF, VEGFR1, and VEGFR2 was assessed immunohistochemically on a cohort of 371 well documented, surgically resected NSCLC using a standardized tissue microarray platform. Extensive clinical data and a postoperative follow-up period of up to 18 years allowed us to assess clinicopathological correlations in detail. Microvasculature in NSCLC was significantly denser at the tumor periphery as compared to the tumor center. Squamous cell carcinomas (SCC) were associated with a notably lower microvessel density (MVD) than adenocarcinomas (ACA). CD105 was present at significantly higher levels on stromal cells of ACA as compared to SCC. Expression of VE-cadherin by tumor cells (6% of cases, mainly ACA) as well as decreased MVD in the tumor centers was independently associated with poor prognosis in the entire cohort. Low MVD in SCC might be related to lower efficacy of and fatal bleeding during therapy with bevacizumab. In other NSCLC entities for which treatment with VEGF inhibitors is studied in clinical trials, the predictive value of MVD for therapy response merits to be prospectively examined. Our data suggest that patients with ACA may be candidates for therapies targeting CD105. VE-cadherin is another promising target for therapy, but its expression also provides independent prognostic information.