Non-small cell lung cancers (NSCLCs) are heterogeneous cancers. In 2004, the 
identification of epidermal growth factor receptor (EGFR) somatic mutations 
provided the first glimpse of a clinically relevant NSCLC oncogene. 
Approximately 70% of NSCLCs with EGFR mutations (exon 19 deletions or the exon 
21 L858R) attain responses to EGFR tyrosine kinase inhibitors (TKIs) gefitinib 
and erlotinib, with improved response rate (RR), progression-free survival (PFS) 
and in some reports overall survival (OS) when compared with EGFR wildtype (WT) 
cases. Three randomized trials of gefitinib versus chemotherapy (IPASS, 
WJTOG3405, NEJ002) in stage IV NSCLC have consistently demonstrated better RR 
and PFS (hazard ratios of 0.48 [IPASS], 0.49 [WJTOG3405] and 0.30 [NEJ002]) for 
EGFR-mutated NSCLCs treated with gefitinib. Novel irreversible EGFR TKIs 
(afatinib, XL647, PF00299804) show similar activity in EGFR-mutated patients. A 
translocation involving the anaplastic lymphoma kinase (ALK) gene with EML4, 
identified in 2007, is the most recent oncogene found in NSCLC. Crizotinib 
(PF02341066), an ALK TKI, has shown impressive activity against ALK translocated 
NSCLC in an expanded cohort of a phase I trial (NCT00585195). Over 80 patients 
have been treated and the RR is ∼60% with the 6-month PFS rate exceeding 70%. A 
registration phase III trial of crizotinib versus second-line chemotherapy 
(pemetrexed/docetaxel) is underway (PROFILE 1007, NCT00932893). KRAS, EGFR 
mutations and ALK translocations are mutually exclusive and few EGFR WT NSCLCs 
respond to EGFR TKIs. The promising results of EGFR and ALK TKIs in molecular 
subgroups of NSCLCs herald a new age of drug and clinical trial development for 
patients with NSCLC.